Compounds and methods for modulating nonclassical cadherin-mediated functions

ABSTRACT

Modulating agents for inhibiting or enhancing nonclassical cadherin mediated cell adhesion are provided. The modulating agents comprise one or more of: (a) a peptide sequence that is at least 50% identical to a nonclassical cadherin CAR sequence; (b) a non-peptide mimetic of a nonclassical cadherin CAR sequence; (c) a substance, such as an antibody or antigen-binding fragment thereof, that specifically binds a nonclassical cadherin CAR sequence; and/or (d) a polynucleotide encoding a polypeptide that comprises a nonclassical cadherin CAR sequence or analogue thereof. Methods for using such modulating agents for modulating nonclassical cadherin-mediated cell adhesion in a variety of contexts are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/839,542, filed Apr. 20, 2001, and allowed Dec. 20, 2002;which is a divisional of U.S. patent application Ser. No. 09/187,859,filed Nov. 6, 1998, now issued as U.S. Pat. No. 6,358,920; which is acontinuation-in-part of U.S. patent application Ser. No. 09/073,040,filed May 5, 1998, now issued as U.S. Pat. No. 6,472,367, whichapplications are incorporated herein by reference in their entireties.

STATEMENT REGARDING SEQUENCE LISTING

[0002] The Sequence Listing associated with this application is providedon CD-ROM in lieu of a paper copy, and is hereby incorporated byreference into the specification. Three CD-ROMs are provided, containingidentical copies of the sequence listing: CD-ROM No. 1 is labeled COPY1, contains the file 407c9.app.txt which is 1.2 MB and created on Mar.21, 2003; CD-ROM No. 2 is labeled COPY 2, contains the file407c9.app.txt which is 1.2 MB and created on Mar. 21, 2003; CD-ROM No. 3is labeled CRF, contains the file 407c9.app.txt which is 1.2 MB andcreated on Mar. 21, 2003.

BACKGROUND OF THE INVENTION

[0003] 1. Field of the Invention

[0004] The present invention relates generally to methods for modulatingnonclassical cadherin-mediated functions, and more particularly to theuse of modulating agents derived from nonclassical cadherin celladhesion recognition sequences for inhibiting or enhancing functionsmediated by nonclassical cadherins.

[0005] 2. Description of the Related Art

[0006] Cadherins are a rapidly expanding superfamily ofcalcium-dependent cell adhesion molecules (CAMs) (for review, see Munroet al., In: Cell Adhesion and Invasion in Cancer Metastasis, P. Brodt,ed., pp. 17-34, RG Landes Co., Austin Tex., 1996). All cadherins appearto be membrane glycoproteins that generally promote cell adhesionthrough homophilic interactions (a cadherin on the surface of one cellbinds to an identical cadherin on the surface of another cell), althoughcadherins also appear to be capable of forming heterotypic complexeswith one another under certain circumstances and with lower affinity.

[0007] There are many different types of cadherins. The most extensivelystudied group of cadherins is known as the classical, or type I,cadherins. Classical cadherins have been shown to regulate epithelial,endothelial, neural and cancer cell adhesion, with different cadherinsexpressed on different cell types. All classical cadherins have asimilar structure. As illustrated in FIG. 1A, classical cadherins arecomposed of five extracellular domains (EC1-EC5), a single hydrophobicdomain (TM) that transverses the plasma membrane (PM), and twocytoplasmic domains (CP1 and CP2). The calcium binding motifs DXNDN (SEQID NO:1), DXD and LDRE (SEQ ID NO:2) are interspersed throughout theextracellular domains, and each 110 amino acid region that contains suchmotifs is considered a cadherin repeat. The first extracellular domain(EC1) contains the cell adhesion recognition (CAR) sequence, HAV(His-Ala-Val), along with flanking sequences on either side of the CARsequence that play a role in conferring specificity. Synthetic peptidescontaining the HAV sequence and antibodies directed against suchpeptides have been shown to inhibit classical cadherin-dependentprocesses (Munro et al., supra; Blaschuk et al., J. Mol. Biol.211:679-82, 1990; Blaschuk et al., Develop. Biol. 139:227-29, 1990;Alexander et al., J. Cell. Physiol. 156:610-18, 1993).

[0008] Cadherins that contain calcium binding motifs withinextracellular domain cadherin repeats, but do not contain an HAV CARsequence, are considered to be nonclassical cadherins (illustrated inFIGS. 1B to 1AA). To date, nine groups of nonclassical cadherins havebeen identified (types II-X). These cadherins are also membraneglycoproteins. Type II, or a typical, cadherins include OB-cadherin(cadherin-11; see Getsios et al., Developmental Dynamics 211:238-247,1998; Simonneau et al., Cell Adhesion and Communication 3:115-130, 1995;Okazaki et al., J. Biological Chemistry 269:12092-12098, 1994),cadherin-5 (VE-cadherin; see Navarro et al., J. Cell Biology140:1475-1484, 1998), cadherin-6 (K-cadherin; see Shimoyama et al.,Cancer Research 55:2206-2211, 1995; Shimazui et al., Cancer Research56:3234-3237, 1996; Inoue et al., Developmental Dynamics 211:338-351,1998; Getsios et al., Developmental Dynamics 211:238-247, 1998),cadherin-7 (see Nakagawa et al., Development 121:1321-1332, 1995),cadherin-8 (see Suzuki et al., Cell Regulation 2:261-270, 1991),cadherin-12 (Br-cadherin; see Tanihara et al., Cell Adhesion andCommunication 2:15-26, 1994), cadherin-14 (see Shibata et al., J.Biological Chemistry 272:5236-5240, 1997), cadherin-15 (M-cadherin; seeShimoyama et al., J. Biological Chemistry 273:10011-10018, 1998), andPB-cadherin (see Sugimoto et al., J. Biological Chemistry271:11548-11556, 1996). For a general review of a typical cadherins, seeRedies and Takeichi, Developmental Biology 180:413-423, 1996 and Suzukiet al., Cell Regulation 2:261-270, 1991.

[0009] Types III-X include LI-cadherin (type III; see Berndorff et al.,J. Cell Biology 125:1353-1369, 1994), T-cadherin (type IV; see Ranscht,U.S. Pat. No. 5,585,351; Tkachuk et al., FEBS Lett. 421:208-212, 1998;Ranscht et al., Neuron 7:391-402, 1991; Sacristan et al., J.Neuroscience Research 34:664-680, 1993; Vestal and Ranscht, J. CellBiology 119:451-461, 1992; Fredette and Ranscht, J. Neuroscience14:7331-7346, 1994; Ranscht and Bronner-Fraser, Development 111:15-22,1991), protocadherins (type V; e.g., protocadherins 42, 43 and 68; seeSano et al., EMBO J. 12:2249-2256, 1993; GenBank Accession NumberAF029343), desmocollins (type VI; e.g., desmocollins 1, 2, 3 and 4; seeKing et al., Genomics 18:185-194, 1993; Parker et al., J. Biol. Chem.266:10438-10445, 1991; King et al., J. Invest. Dermatol. 105:314-321,1995; Kawamura et al., J. Biol. Chem. 269:26295-26302, 1994),desmogleins (type VII; e.g., desmogleins 1 and 2; see Wheeler et al.,Proc. Natl. Acad. Sci. USA 88:4796-4800; Koch et al., Eur. J. Cell.Biol. 55:200-208, 1991), and cadherin-related neuronal receptors (typeX; see Kohmura et al., Neuron 20:1137-1151, 1998).

[0010] Most studies of nonclassical cadherins have focused on a typicalor type II cadherins. The structure of these cadherins is similar tothat of the type I cadherins, but they do not contain the CAR sequence,HAV (FIG. 1B). Furthermore, functions mediated by the a typicalcadherins may be diverse. OB-cadherin, which is also known ascadherin-11, is an a typical cadherin (Getsios et al., DevelopmentalDynamics 211:238-247, 1998; Okazaki et al., J. Biol. Chem. 269:12092-98,1994; Suzuki et al., Cell Regulation 2:261-70, 1991; Munro et al.,supra). This cadherin can promote cell adhesion through homophilicinteractions. Recent studies have shown that OB-cadherin is notexpressed by well-differentiated, poorly invasive cancer cells, whereasit is expressed by invasive cancer cells (et al., Cancer Res.56:3234-37, 1996; Shibata et al., Cancer Letters 99:147-53, 1996).OB-cadherin levels are also high in stromal cells and osteoblasts(Shibata et al., Cancer Letters 99:147-53, 1996; Simonneau et al., CellAdhes. Commun. 3:115-30, 1995; Matsuyoshi and Imamura, Biochem. Biophys.Res. Commun. 23:355-58, 1997; Okazaki et al., J. Biol. Chem.269:12092-98, 1994). Collectively, these observations have led to thehypothesis that OB-cadherin may mediate the interaction betweenmalignant tumor cells and other cell types, such as stromal cells andosteoblasts, thus facilitating tumor cell invasion and metastasis.

[0011] OB-cadherin is expressed in certain specific cell types. In someinvasive cancer cells, OB-cadherin is not only found at sites ofcell-cell contact, but also in lamellopodia-like projections which donot interact with other cells. These observations suggest thatOB-cadherin may also play a role in modulating cell-substrateinteractions. In adipocytes, OB-cadherin is the only known expressedcadherin. OB-cadherin is therefore likely to mediate adhesion betweenadipocytes, and it is likely to be an important regulator ofadipogenesis. Another cell type that expresses OB-cadherin is thepericyte (also known as the peri-endothelial cell). Pericytes arecontractile cells which are similar to smooth muscle cells. Theyencircle the endothelial cells of blood vessels. Pericytes are involvedin maintaining the structural integrity of blood vessels (Hanahan,Science 277:48-50, 1997; Lindahl et al., Science 277:242-245, 1997).Loss of pericytes causes blood vessels to regress.

[0012] Other a typical cadherins appear to have different functions. Forexample, cadherin-5 (also referred to as VE-cadherin) appears to beinvolved in endothelial cell adhesion and cadherin-6 (also referred toas K-cadherin) may be involved in embryonic kidney cell adhesion and isup-regulated in kidney cancer. Cadherin-15 also appears to play a rolein the terminal differentiation of muscle cells.

[0013] Notwithstanding these recent advances, nonclassical cadherinfunction remains poorly understood at the biological and molecularlevels. Accordingly, there is a need in the art for identifyingsequences involved in modulating nonclassical cadherin-dependentfunctions, such as cell adhesion, and for the development of methodsemploying such sequences to inhibit processes such as cancer celladhesion, invasion and metastasis. The present invention fulfills theseneeds and further provides other related advantages.

BRIEF SUMMARY OF THE INVENTION

[0014] Briefly stated, this invention provides compositions and methodsfor modulating nonclassical cadherin-mediated functions, such as cancercell adhesion, invasion, and metastasis. Within certain aspects,modulating agents capable of modulating (i.e., inhibiting or enhancing)one or more functions mediated by a nonclassical cadherin are provided.Such modulating agents generally: (a) comprise a peptide sequence thatis at least 50% identical to a nonclassical cadherin CAR sequence; (b)modulate a function mediated by the nonclassical cadherin, such that themodulating agent: (i) detectably inhibits a function that is modulatedby the nonclassical cadherin; or (ii) detectably enhances adhesion ofcells that express the nonclassical cadherin; and (c) contain no morethan 85, and preferably no more than 50, consecutive amino acid residuespresent within the nonclassical cadherin. Certain modulating agentscomprise a nonclassical cadherin CAR sequence and are 3-16 amino acidresidues in length.

[0015] For certain modulating agents as provided above, the nonclassicalcadherin CAR sequence has the formula:

[0016] Aaa-Phe-Baa-IIe/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQID NO:3)

[0017] wherein Aaa, Baa, Caa and Daa are independently selected aminoacid residues; IIe/Leu/Val is an amino acid that is selected from thegroup consisting of isoleucine, leucine and valine, Asp/Asn/Glu is anamino acid that is selected from the group consisting of aspartate,asparagine and glutamate; and Ser/Thr/Asn is an amino acid that isselected from the group consisting of serine, threonine or asparagine.For other modulating agents as described above, the nonclassicalcadherin CAR sequence consists of at least three consecutive amino acidresidues, and preferably at least five consecutive amino acid residues,of a nonclassical cadherin, wherein the consecutive amino acids arepresent within a region of the nonclassical cadherin having the formularecited above. Other modulating agents may comprise at least nineconsecutive amino acid residues of a nonclassical cadherin, wherein thenine consecutive amino acid residues comprise a region having a formulaas recited above.

[0018] Within certain specific embodiments, a modulating agent asdescribed above is a peptide ranging in size from 3 to 50, preferablyfrom 4 to 16, amino acid residues.

[0019] Within other embodiments, a modulating agent comprises anonclassical cadherin CAR sequence that is present within a cyclicpeptide. Such cyclic peptides may have the formula:

[0020] wherein W is a tripeptide selected from the group consisting ofEEY, DDK, EAQ, DAE, NEN, ESE, DSG, DEN, EPK, DAN, EEF, NDV, DET, DPK,DDT, DAN, DKF, DEL, DAD, NNK, DLV, NRD, DPS, NQK, NRN, NKD, EKD, ERD,DPV, DSV, DLY, DSN, DSS, DEK and NEK; wherein X₁, and X₂ are optional,and if present, are independently selected from the group consisting ofamino acid residues and combinations thereof in which the residues arelinked by peptide bonds, and wherein X₁ and X₂ independently range insize from 0 to 10 residues, such that the sum of residues containedwithin X₁ and X₂ ranges from 1 to 12; wherein Y₁ and Y₂ areindependently selected from the group consisting of amino acid residues,and wherein a covalent bond is formed between residues Y₁ and Y₂; andwherein Z₁ and Z₂ are optional, and if present, are independentlyselected from the group consisting of amino acid residues andcombinations thereof in which the residues are linked by peptide bonds.

[0021] Within other aspects of the present invention, polynucleotidesencoding a modulating agent as described above are provided, along withexpression vectors comprising such a polynucleotide and host cellstransformed or transfected with such an expression vector.

[0022] The present invention further provides modulating agents thatcomprise an antibody or antigen-binding fragment thereof thatspecifically binds to a nonclassical cadherin CAR sequence and modulatesa nonclassical cadherin-mediated function, wherein the nonclassicalcadherin CAR sequence has the formula:Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

[0023] wherein Aaa, Baa, Caa and Daa are independently selected aminoacid residues; IIe/Leu/Val is an amino acid that is selected from thegroup consisting of isoleucine, leucine and valine, Asp/Asn/Glu is anamino acid that is selected from the group consisting of aspartate,asparagine and glutamate; and Ser/Thr/Asn is an amino acid that isselected from the group consisting of serine, threonine and asparagine;and wherein the modulating agent inhibits or enhances a functionmediated by the nonclassical cadherin. Within specific embodiments, thenonclassical cadherin CAR sequence may be any of the sequences recitedbelow.

[0024] Within further aspects, the present invention provides modulatingagents comprising a non-peptide mimetic of any one of the nonclassicalcadherin CAR sequences provided above.

[0025] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more OB-cadherin CAR sequencesselected from the group consisting of DDK, IDDK (SEQ ID NO:4051) DDKS(SEQ ID NO:73), VIDDK (SEQ ID NO:74), IDDKS (SEQ ID NO:75), VIDDKS (SEQID NO:76), DDKSG (SEQ ID NO:77), IDDKSG (SEQ ID NO:78), VIDDKSG (SEQ IDNO:79), FVIDDK (SEQ ID NO:80), FVIDDKS (SEQ ID NO:81), FVIDDKSG (SEQ IDNO:82), IFVIDDK (SEQ ID NO:83), IFVIDDKS (SEQ ID NO:84), IFVIDDKSG (SEQID NO:85), EEY, IEEY (SEQ ID NO:86), EEYT (SEQ ID NO:87), VIEEY (SEQ IDNO:88), IEEYT (SEQ ID NO:89), VIEEYT (SEQ ID NO:90), EEYTG (SEQ IDNO:91), IEEYTG (SEQ ID NO:92), VIEEYTG (SEQ ID NO:93), FVIEEY (SEQ IDNO:94), FVIEEYT (SEQ ID NO:95), FVIEEYTG (SEQ ID NO:96), FFVIEEY (SEQ IDNO:97), FFVIEEYT (SEQ ID NO:98), FFVIEEYTG (SEQ ID NO:99), EAQ, VEAQ(SEQ ID NO:100), EAQT (SEQ ID NO:101), SVEAQ (SEQ ID NO:102), VEAQT (SEQID NO:103), SVEAQT (SEQ ID NO:104), EAQTG (SEQ ID NO:105), VEAQTG (SEQID NO:106), SVEAQTG (SEQ ID NO:107), FSVEAQ (SEQ ID NO:108), FSVEAQT(SEQ ID NO:109), FSVEAQTG (SEQ ID NO:110), YFSVEAQ (SEQ ID NO:111),YFSVEAQT (SEQ ID NOl 12) and YFSVEAQTG (SEQ ID NO:113); or (b) ananalogue of any of the foregoing sequences that differs in one or moresubstitutions, deletions, additions and/or insertions such that thatability of the analogue to modulate an OB-cadherin-mediated function isnot substantially diminished. For example, the agent may comprise alinear peptide having the sequence N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85),N-Ac-FFVIEEYTG-NH₂ (SEQ ID NO:99) or N-Ac-YFSVEAQTG-NH₂ (SEQ ID NO:113).The OB-cadherin CAR sequence may, but need not, be present within acyclic peptide.

[0026] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-5 CAR sequencesselected from the group consisting of DAE, VDAE (SEQ ID NO:114), DAET(SEQ ID NO:115), RVDAE (SEQ ID NO:116), VDAET (SEQ ID NO:117), RVDAET(SEQ ID NO:118), DAETG (SEQ ID NO:119), VDAETG (SEQ ID NO:120), RVDAETG(SEQ ID NO:121), FRVDAE (SEQ ID NO:122), FRVDAET (SEQ ID NO:123),FRVDAETG (SEQ ID NO:124), VFRVDAE (SEQ ID NO:125), VFRVDAET (SEQ IDNO:126) and VFRVDAETG (SEQ ID NO:127); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-5-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-VFRVDAETG-NH₂ (SEQ ID NO:127). The cadherin-5 CARsequence may, but need not, be present within a cyclic peptide.

[0027] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-6 CAR sequencesselected from the group consisting of NEN, INEN (SEQ ID NO128), NENT(SEQ ID NO:129), IINEN (SEQ ID NO:130), INENT (SEQ ID NO:131), IINENT(SEQ ID NO:132), NENTG (SEQ ID NO:133), INENTG (SEQ ID NO:134), IINENTG(SEQ ID NO:135), FIINEN (SEQ ID NO:136), FIINENT (SEQ ID NO:137),FIINENTG (SEQ ID NO:138), LFIINEN (SEQ ID NO:139), LFIINENT (SEQ IDNO:140), LFIINENTG (SEQ ID NO:141), EEY, EEYT (SEQ ID NO:142), EEYTG(SEQ ID NO:143), LEEY (SEQ ID NO:144), LEEYT (SEQ ID NO:145), LEEYTG(SEQ ID NO:146), LLEEY (SEQ ID NO:147), LLEEYTG (SEQ ID NO:148), FLLEEY(SEQ ID NO:149), FLLEEYT (SEQ ID NO:150), FLLEEYTG (SEQ ID NO:151),FFLLEEY (SEQ ID NO:152), FFLLEEYT (SEQ ID NO:153), FFLLEEYTG (SEQ IDNO:154), ESE, ESET (SEQ ID NO:155), ESETG (SEQ ID NO:156), VESE (SEQ IDNO:157), VSEST (SEQ ID NO:158), VESETG (SEQ ID NO:159), SVESE (SEQ IDNO:160), SVESET (SEQ ID NO:161), SVESETG (SEQ ID NO:162), FSVESE (SEQ IDNO:163), FSVESET (SEQ ID NO:164), FSVESETG (SEQ ID NO:165), YFSVESE (SEQID NO:166), YFSVESET (SEQ ID NO:167), YFSVESETG (SEQ ID NO:168), DSG,DSGN (SEQ ID NO:169), DSGNG (SEQ ID NO:170), IDSG (SEQ ID NO:171), IDSGN(SEQ ID NO:172), IDSGNG (SEQ ID NO:173), NIDSG (SEQ ID NO:174), NIDSGN(SEQ ID NO:175), NIDSGNG (SEQ ID NO:176), FNIDSG (SEQ ID NO:177),FNIDSGN (SEQ ID NO:178), FNIDSGNG (SEQ ID NO:179), IFNIDSG (SEQ IDNO:180), IFNIDSGN (SEQ ID NO:181) and IFNIDSGNG (SEQ ID NO:182); or (b)an analogue of any of the foregoing sequences that differs in one ormore substitutions, deletions, additions and/or insertions such thatthat ability of the analogue to modulate a cadherin-6-mediated functionis not substantially diminished. For example, the agent may comprise alinear peptide having the sequence N-Ac-FFLLEEYTG-NH₂ (SEQ ID NO:154),N-Ac-LFIINENTG-NH₂ (SEQ ID NO:141),N-Ac-YFSVESETG-NH₂ (SEQ ID NO:168) orN-Ac-IFNIDSGNG-NH₂ (SEQ ID NO:187). The cadherin-6 CAR sequence may, butneed not, be present within a cyclic peptide.

[0028] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-7 CAR sequencesselected from the group consisting of DEN, IDEN (SEQ ID NO:183), DENT(SEQ ID NO:184), IIDEN (SEQ ID NO:185), IDENT (SEQ ID NO:186), IIDENT(SEQ ID NO:187), DENTG (SEQ ID NO:188), IDENTG (SEQ ID NO:189), IIDENTG(SEQ ID NO:190), FIIDEN (SEQ ID NO:191), FIIDENT (SEQ ID NO:192),FIIDENTG (SEQ ID NO:193), IFIIDEN (SEQ ID NO:194), IFIIDENT (SEQ IDNO:195), IFIIDENTG (SEQ ID NO:196), EPK, EPKT (SEQ ID NO:197), EPKTG(SEQ ID NO:198), VEPK (SEQ ID NO:199), VEPKT (SEQ ID NO:200), VEPKTG(SEQ ID NO:201), SVEPK (SEQ ID NO:202), SVEPKT (SEQ ID NO:203), SVEPKTG(SEQ ID NO:204), FSVEPK (SEQ ID NO:205), FSVEPKT (SEQ ID NO:206),FSVEPKTG (SEQ ID NO:207), YFSVEPK (SEQ ID NO:208), YFSVEPKT (SEQ IDNO:209), YFSVEPKTG (SEQ ID NO:210), DAN, DANS (SEQ ID NO:211), DANSG(SEQ ID NO:212), IDAN (SEQ ID NO:213), IDANS (SEQ ID NO:214), IDANSG(SEQ ID NO:215), NIDAN (SEQ ID NO:216), NIDANS (SEQ ID NO:217), NIDANSG(SEQ ID NO:218), FNIDAN (SEQ ID NO:219), FNIDANS (SEQ ID NO:220),FNIDANSG (SEQ ID NO:221), YFNIDAN (SEQ ID NO:222), YFNIDANS (SEQ IDNO:223) and YFNIDANSG (SEQ ID NO:224); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-7-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-IFIIDENTG-NH₂ (SEQ ID NO:196), N-Ac-YFSVEPKTG-NH₂ (SEQID NO:210) or N-Ac-YFNIDANSG-NH₂ (SEQ ID NO:224). The cadherin-7 CARsequence may, but need not, be present within a cyclic peptide.

[0029] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-8 CAR sequencesselected from the group consisting of NDV, INDV (SEQ ID NO:225), NDVT(SEQ ID NO:226), QINDV (SEQ ID NO:227), INDVT (SEQ ID NO:228), QINDVT(SEQ ID NO:229), NDVTG (SEQ ID NO:230), INDVTG (SEQ ID NO:231), QINDVTG(SEQ ID NO:232), FQINDV (SEQ ID NO:233), FQINDVT (SEQ ID NO:234),FQINDVTG (SEQ ID NO:235), IFQINDV (SEQ ID NO:236), IFQINDVT (SEQ IDNO:237), IFQINDVTG (SEQ ID NO:238), EEF, EEFS (SEQ ID NO:239), EEFSG(SEQ ID NO:240), LEEF (SEQ ID NO:241), LEEFS (SEQ ID NO:242), LEEFSG(SEQ ID NO:243), VLEEF (SEQ ID NO:244), VLEEFS (SEQ ID NO:245), VLEEFSG(SEQ ID NO:247), FVLEEF (SEQ ID NO:247), FVLEEFS (SEQ ID NO:248),FVLEEFSG (SEQ ID NO:249), MFVLEEF (SEQ ID NO:250), MFVLEEFS (SEQ IDNO:251) and MFVLEEFSG (SEQ ID NO:252); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-8-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-MFVLEEFSG-NH₂ (SEQ ID NO:252) or N-Ac-IFQINDVTG-NH₂(SEQ ID NO:238). The cadherin-8 CAR sequence may, but need not, bepresent within a cyclic peptide.

[0030] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-12 CAR sequencesselected from the group consisting of DET, IDET (SEQ ID NO:253), DETT(SEQ ID NO:254), TIDET (SEQ ID NO:255), IDETT (SEQ ID NO:256), TIDETT(SEQ ID NO:257), DETTG (SEQ ID NO:258), IDETTG (SEQ ID NO:259), TIDETTG(SEQ ID NO:260), FTIDET (SEQ ID NO:261), FTIDETT (SEQ ID NO:262),FTIDETTG (SEQ ID NO:263), VFTIDET (SEQ ID NO:264), VFTIDETT (SEQ IDNO:265), VFTIDETTG (SEQ ID NO:266), DPK, DPKT (SEQ ID NO:267), DPKTG(SEQ ID NO:268), IDPK (SEQ ID NO:269), IDPKT (SEQ ID NO:270), IDPKTG(SEQ ID NO:271), SIDPK (SEQ ID NO:272), SIDPKT (SEQ ID NO:273), SIDPKTG(SEQ ID NO:274), FSIDPK (SEQ ID NO:275), FSIDPKT (SEQ ID NO:276),FSIDPKTG (SEQ ID NO:277), YFSIDPK (SEQ ID NO:278), YFSIDPKT (SEQ IDNO:279) and YFSIDPKTG (SEQ ID NO:280); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-12-mediated function is notsubstantially diminished. For example, the agent may comprise a linearpeptide having the sequence N-Ac-VFTIDETTG-NH₂ (SEQ ID NO:266) orN-Ac-YFSIDPKTG-NH₂ (SEQ ID NO:280). The cadherin-12 CAR sequence may,but need not, be present within a cyclic peptide.

[0031] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-14 CAR sequencesselected from the group consisting of DDT, IDDT (SEQ ID NO:281), DDTT(SEQ ID NO:282), IIDDT (SEQ ID NO:283), IDDTT (SEQ ID NO:284), IIDDTT(SEQ ID NO:285), DDTTG (SEQ ID NO:286), IDDTTG (SEQ ID NO:287), IIDDTTG(SEQ ID NO:288), FIIDDT (SEQ ID NO:289), FIIDDTT (SEQ ID NO:290),FIIDDTTG (SEQ ID NO:291), IFIIDDT (SEQ ID NO:292), IFIIDDTT (SEQ IDNO:293), IFIIDDTTG (SEQ ID NO:294), DPK, DPKT (SEQ ID NO:295), DPKTG(SEQ ID NO:296), VDPK (SEQ ID NO:297), VDPKT (SEQ ID NO:298), VDPKTG(SEQ ID NO:299), SVDPK (SEQ ID NO:300), SVDPKT (SEQ ID NO:301), SVDPKTG(SEQ ID NO:302), FSVDPK (SEQ ID NO:303), FSVDPKT (SEQ ID NO:304),FSVDPKTG (SEQ ID NO:305), YFSVDPK (SEQ ID NO:306), YFSVDPKT (SEQ IDNO:307), YFSVDPKTG (SEQ ID NO:308), DAN, DANT (SEQ ID NO:309), DANTG(SEQ ID NO:310), IDANT (SEQ ID NO:311), IDANTG (SEQ ID NO:312), NIDANT(SEQ ID NO:313), NIDANTG (SEQ ID NO:314), FNIDANT (SEQ ID NO:315),FNIDANTG (SEQ ID NO:316), FFNIDAN (SEQ ID NO:317), FFNIDANT (SEQ IDNO:318) and FFNIDANTG (SEQ ID NO:319); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-14-mediated function is notsubstantially diminished. For example, the agent may comprise a linearpeptide having the sequence N-Ac-IFIIDDTTG-NH₂ (SEQ ID NO:294),N-Ac-YFSVDPKTG-NH₂ (SEQ ID NO:308) or N-Ac-FFNIDANTG-NH₂ (SEQ IDNO:319). The cadherin-14 CAR sequence may, but need not, be presentwithin a cyclic peptide.

[0032] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more cadherin-15 CAR sequencesselected from the group consisting of DKF, IDKF (SEQ ID NO:320), DKFT(SEQ ID NO:321), SIDKF (SEQ ID NO:322), IDKFT (SEQ ID NO:323), SIDKFT(SEQ ID NO:324), DKFTG (SEQ ID NO:325), IDKFTG (SEQ ID NO:326), SIDKFTG(SEQ ID NO:327), FSIDKF (SEQ ID NO:328), FSIDKFT (SEQ ID NO:329),FSIDKFTG (SEQ ID NO:330), VFSIDKF (SEQ ID NO:331), VFSIDKFT (SEQ IDNO:332), VFSIDKFTG (SEQ ID NO:333), DEL, DELT (SEQ ID NO:334), DELTG(SEQ ID NO:335), IDEL (SEQ ID NO:336), IDELT (SEQ ID NO:337), IDELTG(SEQ ID NO:338), SIDEL (SEQ ID NO:339), SIDELT (SEQ ID NO:340), SIDELTG(SEQ ID NO:341), FSIDEL (SEQ ID NO:342), FSIDELT (SEQ ID NO:343),FSIDELTG (SEQ ID NO:344), LFSIDEL (SEQ ID NO:345), LFSIDELT (SEQ IDNO:346) and LFSIDELTG (SEQ ID NO:347); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a cadherin-15-mediated function is notsubstantially diminished. For example, the agent may comprise a linearpeptide having the sequence N-Ac-VFSIDKFTG-NH₂ (SEQ ID NO:333) orN-Ac-LFSIDELTG-NH₂ (SEQ ID NO:347). The cadherin-15 CAR sequence may,but need not, be present within a cyclic peptide.

[0033] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more T-cadherin CAR sequencesselected from the group consisting of NEN, INEN (SEQ ID NO:348), NENT(SEQ ID NO:349), RINEN (SEQ ID NO:350), INENT (SEQ ID NO:351), RINENT(SEQ ID NO:352), NENTG (SEQ ID NO:353), INENTG (SEQ ID NO:354), RINENTG(SEQ ID NO:355), FRINEN (SEQ ID NO:356), FRINENT (SEQ ID NO:357),FRINENTG (SEQ ID NO:358), IFRINEN (SEQ ID NO:359), IFRINENT (SEQ IDNO:360) and IFRINENTG (SEQ ID NO:361); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a T-cadherin-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-IFRINENTG-NH₂ (SEQ ID NO:361). The T-cadherin CARsequence may, but need not, be present within a cyclic peptide.

[0034] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more PB-cadherin CAR sequencesselected from the group consisting of EEY, EEYT (SEQ ID NO:362), EEYTG(SEQ ID NO:363), VEEY (SEQ ID NO:364), VEEYT (SEQ ID NO:365), VEEYTG(SEQ ID NO:366), VVEEY (SEQ ID NO:367), VVEEYT (SEQ ID NO:368), VVEEYTG(SEQ ID NO:369), FVVEEY (SEQ ID NO:370), FVEEYT (SEQ ID NO:371), FVEEYTG(SEQ ID NO:372), FFVVEEY (SEQ ID NO:373), FFVVEEYT (SEQ ID NO:374),FFVVEEYTG (SEQ ID NO:375), DEL, DELT (SEQ ID NO:376), DELTG (SEQ IDNO:377), IDEL (SEQ ID NO:378), IDELT (SEQ ID NO:379), IDELTG (SEQ IDNO:380), LIDEL (SEQ ID NO:381), LIDELT (SEQ ID NO:382), LIDELTG (SEQ IDNO:383), FLIDEL (SEQ ID NO:384), FLIDELT (SEQ ID NO:385), FLIDELTG (SEQID NO:386), IFLIDEL (SEQ ID NO:387), IFLIDELT (SEQ ID NO:388), IFLIDELTG(SEQ ID NO:389), DPK, DPKT (SEQ ID NO:390), DPKTG (SEQ ID NO:391), VDPK(SEQ ID NO:392), VDPKT (SEQ ID NO:393), VDPKTG (SEQ ID NO:394), TVDPK(SEQ ID NO:395), TVDPKT (SEQ ID NO:396), TVDPKTG (SEQ ID NO:397), FTVDPK(SEQ ID NO:398), FTVDPKT (SEQ ID NO:399), FTVDPKTG (SEQ ID NO:400),HFTVDPK (SEQ ID NO:401), HFTVDPKT (SEQ ID NO:402), HFTVDPKTG (SEQ IDNO:403), DAD, DADT (SEQ ID NO:404), DADTG (SEQ ID NO:405), IDAD (SEQ IDNO:406), IDADT (SEQ ID NO:407), IDADTG (SEQ ID NO:408), DIDAD (SEQ IDNO:409), DIDADT (SEQ ID NO:410), DIDADTG (SEQ ID NO:411), FDIDAD (SEQ IDNO:412), FDIDADT (SEQ ID NO:413), FDIDADTG (SEQ ID NO:414), IFDIDAD (SEQID NO:415), IFDIDADT (SEQ ID NO:416) and IFDIDADTG (SEQ ID NO:417); or(b) an analogue of any of the foregoing sequences that differs in one ormore substitutions, deletions, additions and/or insertions such thatthat ability of the analogue to modulate a PB-cadherin-mediated functionis not substantially diminished. For example, the agent may comprise alinear peptide having the sequence N-Ac-FFVVEEYTG-NH₂ (SEQ ID NO:375),N-Ac-IFLIDELTG-NH₂ (SEQ ID NO:389), N-Ac-HFTVDPKTG-NH₂ (SEQ ID NO:403)or N-Ac-IFDIDADTG-NH₂ (SEQ ID NO:417). The PB-cadherin CAR sequence may,but need not, be present within a cyclic peptide.

[0035] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more LI-cadherin CAR sequencesselected from the group consisting of NNK, NNKT (SEQ ID NO:418), NNKTG(SEQ ID NO:419), INNK (SEQ ID NO:420), INNKT (SEQ ID NO:421), INNKTG(SEQ ID NO:422), QINNK (SEQ ID NO:423), QINNKT (SEQ ID NO:424), QINNKTG(SEQ ID NO:425), FQINNK (SEQ ID NO:426), FQINNKT (SEQ ID NO:427),FQINNKTG (SEQ ID NO:428), YFQINNK (SEQ ID NO:429), YFQINNKT (SEQ IDNO:430) and YFQINNKTG (SEQ ID NO:431); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a LI-cadherin-mediated function is notsubstantially diminished. For example, the agent may comprise a linearpeptide having the sequence N-Ac-YFQINNKTG-NH₂ (SEQ ID NO:431). TheLI-cadherin CAR sequence may, but need not, be present within a cyclicpeptide.

[0036] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more protocadherin CARsequences selected from the group consisting of DLV, DLVT (SEQ IDNO:432), DLVTG (SEQ ID NO:433), LDLV (SEQ ID NO:434), LDLVT (SEQ IDNO:435), LDLVTG (SEQ ID NO:436), ALDLV (SEQ ID NO:437), ALDLVT (SEQ IDNO:438), ALDLVTG (SEQ ID NO:439), FALDLV (SEQ ID NO:440), FALDLVT (SEQID NO:441), FALDLVTG (SEQ ID NO:442), LFALDLV (SEQ ID NO:443), LFALDLVT(SEQ ID NO:444), LFALDLVTG (SEQ ID NO:445), NRD, NRDN (SEQ ID NO:446),NRDNG (SEQ ID NO:447), INRD (SEQ ID NO:448), INRDN (SEQ ID NO:449),INRDNG (SEQ ID NO:450), TINRD (SEQ ID NO:451), TINRDN (SEQ ID NO:452),TINRDNG (SEQ ID NO:453), FTINRD (SEQ ID NO:454), FTINRDN (SEQ IDNO:455), FTINRDNG (SEQ ID NO:456), YFTINRD (SEQ ID NO:457), YFTINRDN(SEQ ID NO:458), YFTINRDNG (SEQ ID NO:459), DPK, DPKT (SEQ ID NO:460),DPKTG (SEQ ID NO:461), IDPK (SEQ ID N.0:462), IDPKT (SEQ ID NO:463),IDPKTG (SEQ ID NO:464), SIDPK (SEQ ID NO:465), SIDPKT (SEQ ID NO:466),SIDPKTG (SEQ ID NO:467), FSIDPK (SEQ ID NO:468), FSIDPKT (SEQ IDNO:469), FSIDPKTG (SEQ ID NO:470), LFSIDPK (SEQ ID NO:471), LFSIDPKT(SEQ ID NO:472), LFSIDPKTG (SEQ ID NO:473), DPS, DPSS (SEQ ID NO:474),DPSSG (SEQ ID NO:475), IDPS (SEQ ID NO:476), IDPSS (SEQ ID NO:477),IDPSSG (SEQ ID NO:478), EIDPS (SEQ ID NO:479), EIDPSS (SEQ ID NO:480),EIDPSSG-(SEQ ID NO:481), FEIDPS (SEQ ID NO:482), FEIDPSS (SEQ IDNO:483), FEIDPS (SEQ ID NO:484), FEIDPSS (SEQ ID NO:485), FEIDPSSG (SEQID NO:486), LFEIDPS (SEQ ID NO:487), LFEIDPSS (SEQ ID NO:488) andLFEIDPSSG (SEQ ID NO:489); or (b) an analogue of any of the foregoingsequences that differs in one or more substitutions, deletions,additions and/or insertions such that that ability of the analogue tomodulate a protocadherin-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-LFALDLVTG-NH₂ (SEQ ID NO:445), N-Ac-YFTINRDNG-NH₂ (SEQID NO:459), N-Ac-LFSIDPKTG-NH₂ (SEQ ID NO:473) or N-Ac-LFEIDPSSG-NH₂(SEQ ID NO:489). The protocadherin CAR sequence may, but need not, bepresent within a cyclic peptide.

[0037] Within certain specific embodiments, a modulating agent asprovided herein comprises: (a) one or more desmoglein CAR sequencesselected from the group consisting of NQK, NQKT (SEQ ID NO:490), NQKTG(SEQ ID NO:491), INQK (SEQ ID NO:492), INQKT (SEQ ID NO:493), INQKTG(SEQ ID NO:494), VINQK (SEQ ID NO:495), VINQKT (SEQ ID NO:496), VINQKTG(SEQ ID NO:497), FVINQK (SEQ ID NO:498), FVINQKT (SEQ ID NO:499),FVINQKTG (SEQ ID NO:500), IFVINQK (SEQ ID NO:501), IFVINQKT (SEQ IDNO:502), IFVINQKTG (SEQ ID NO:503), NRN, NRNT (SEQ ID NO:504), NRNTG(SEQ ID NO:505), INRN (SEQ ID NO:506), INRNT (SEQ ID NO:507), INRNTG(SEQ ID NO:508), IINRN (SEQ ID NO:509), IINRNT (SEQ ID NO:510), IINRNTG(SEQ ID NO:511), FIINRN (SEQ ID NO:512), FIINRNT (SEQ ID NO:513),FIINRNTG (SEQ ID NO:514), MFIINRN (SEQ ID NO:515), MFIINRNT (SEQ IDNO:516), MFIINRNTG (SEQ ID NO:517), NKD, NKDT (SEQ ID NO:518), NKDTG(SEQ ID NO:519), LNKD (SEQ ID NO:520), LNKDT (SEQ ID NO:521), LNKDTG(SEQ ID NO:522), YLNKD (SEQ ID NO:523), YLNKDT (SEQ ID NO:524), YLNKDTG(SEQ ID NO:525), FYLNKD (SEQ ID NO:526), FYLNKDT (SEQ ID NO:527),FYLNKDTG (SEQ ID NO:528), VFYLNKD (SEQ ID NO:529), VFYLNKDT (SEQ IDNO:530) and VFYLNKDTG (SEQ ID NO:531); or (b) an analogue of any of theforegoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a desmoglein-mediated function is not substantiallydiminished. For example, the agent may comprise a linear peptide havingthe sequence N-Ac-IFVINQKTG-NH₂ (SEQ ID NO:503), N-Ac-MFIINRNTG-NH₂ (SEQID NO:517) or N-Ac-VFYLNKDTG-NH₂ (SEQ ID NO:531). The desmoglein CARsequence may, but need not, be present within a cyclic peptide.

[0038] Within certain specific embodiments, a modulating agent asprovided herein may comprise: (a) one or more desmocollin CAR sequencesselected from the group consisting of EKD, EKDT (SEQ ID NO:532), EKDTG(SEQ ID NO:533), IEKD (SEQ ID NO:534), IEKDT (SEQ ID NO:535), IEKDTG(SEQ ID NO:536), YIEKD (SEQ ID NO:537), YIEKDT (SEQ ID NO:538), YIEKDTG(SEQ ID NO:539), FYIEKD (SEQ ID NO:540), FYIEKDT (SEQ ID NO:541),FYIEKDTG (SEQ ID NO:542), LFYIEKD (SEQ ID NO:543), LFYIEKDT (SEQ IDNO:544), LFYIEKDTG (SEQ ID NO:545), ERD, ERDT (SEQ ID NO:546), ERDTG(SEQ ID NO:547), VERD (SEQ ID NO:548), VERDT (SEQ ID NO:549), VERDTG(SEQ ID NO:550), YVERD (SEQ ID NO:551), YVERDT (SEQ ID NO:552), YVERDTG(SEQ ID NO:553), FYVERD (SEQ ID NO:554), FYVERDT (SEQ ID NO:555),FYVERDTG (SEQ ID NO:556), LFYVERD (SEQ ID NO:557), LFYVERDT (SEQ IDNO:558), LFYVERDTG (SEQ ID NO:559), IERD (SEQ ID NO:560), IERDT (SEQ IDNO:561), IERDTG (SEQ ID NO:562), YIERD (SEQ ID NO:563), YIERDT (SEQ IDNO:564), YIERDTG (SEQ ID NO:565), FYIERD (SEQ ID NO:566), FYIERDT (SEQID NO:567), FYIERDTG (SEQ ID NO:568), LFYIERD (SEQ ID NO:569), LFYIERDT(SEQ ID NO:570) and LFYIERDTG (SEQ ID NO:571); or (b) an analogue of anyof the foregoing sequences that differs in one or more substitutions,deletions, additions and/or insertions such that that ability of theanalogue to modulate a desmocollin-mediated function is notsubstantially diminished. For example, the agent may comprise a linearpeptide having the sequence N-Ac-LFYIEKDTG-NH₂ (SEQ ID NO:545),N-Ac-LFYVERDTG-NH₂ (SEQ ID NO:559) or N-Ac-LFYIERDTG-NH₂ (SEQ IDNO:571). The desmocollin CAR sequence may, but need not, be presentwithin a cyclic peptide.

[0039] Within certain specific embodiments, a modulating agent asprovided herein comprises: (a) one or more cadherin-related neuronalreceptor (cnr) CAR sequences selected from the group consisting of DPV,DPVS (SEQ ID NO:572), DPVSG (SEQ ID NO:573), IDPV (SEQ ID NO:574), IDPVS(SEQ ID NO:575), IDPVSG (SEQ ID NO:576), HIDPV (SEQ ID NO:577), HIDPVS(SEQ ID NO:578), HIDPVSG (SEQ ID NO:579), FHIDPV (SEQ ID NO:580),FHIDPVS (SEQ ID NO:581), FHIDPVSG (SEQ ID NO:582), KFHIDPV (SEQ IDNO:583), KFHIDPVS (SEQ ID NO:584), KFHIDPVSG (SEQ ID NO:585), DAD, DADT(SEQ ID NO:586), DADTG (SEQ ID NO:587), IDAD (SEQ ID NO:588), IDADT (SEQID NO:589), IDADTG (SEQ ID NO:590), SIDAD (SEQ ID NO:591), SIDADT (SEQID NO:592), SIDADTG (SEQ ID NO:593), FSIDAD (SEQ ID NO:594), FSIDADT(SEQ ID NO:595), FSIDADTG (SEQ ID NO:596), QFSIDAD (SEQ ID NO:597),QFSIDADT (SEQ ID NO:598), QFSIDADTG (SEQ ID NO:599), DSV, DSVS (SEQ IDNO:600), DSVSG (SEQ ID NO:601), IDSV (SEQ ID NO:602), IDSVS (SEQ IDNO:603), IDSVSG (SEQ ID NO:604), HIDSV (SEQ ID NO:605), HIDSVS (SEQ IDNO:606), HIDSVSG (SEQ ID NO:607), FHIDSV (SEQ ID NO:608), FHIDSVS (SEQID NO:609), FHIDSVSG (SEQ ID NO:610), TFHIDSV (SEQ ID NO:611), TFHIDSVS(SEQ ID NO:612), TFHIDSVSG (SEQ ID NO:613), DSN, DSNS (SEQ ID NO:614),DSNSG (SEQ ID NO:615), IDSN (SEQ ID NO:616), IDSNS (SEQ ID NO:617),IDSNSG (SEQ ID NO:618), NIDSN (SEQ ID NO:619), NIDSNS (SEQ ID NO:620),NIDSNSG (SEQ ID NO:621), FNIDSN (SEQ ID NO:622), FNIDSNS (SEQ IDNO:623), FNIDSNSG (SEQ ID NO:624), AFNIDSN (SEQ ID NO:625), AFNIDSNS(SEQ ID NO:626), AFNIDSNSG (SEQ ID NO:627), DSS, DSSS (SEQ ID NO:628),DSSSG (SEQ ID NO:629), IDSS (SEQ ID NO:630), IDSSS (SEQ ID NO:631),IDSSSG (SEQ ID NO:632), TIDSS (SEQ ID NO:633), TIDSSS (SEQ ID NO:634),TIDSSSG (SEQ ID NO:635), FTIDSS (SEQ ID NO:636), FTIDSSS (SEQ IDNO:637), FTIDSSSG (SEQ ID NO:638), KFTIDSS (SEQ ID NO:639), KFTIDSSS(SEQ ID NO:640), KFTIDSSSG (SEQ ID NO:641), DEK, DEKN (SEQ ID NO:642),DEKNG (SEQ ID NO:643), LDEK (SEQ ID NO:644), LDEKN (SEQ ID NO:645),LDEKNG (SEQ ID NO:646), TLDEK (SEQ ID NO:647), TLDEKN (SEQ ID NO:648),TLDEKNG (SEQ ID NO:649), FTLDEK (SEQ ID NO:650), FTLDEKN (SEQ IDNO:651), FTLDEKNG (SEQ ID NO:652), LFTLDEK (SEQ ID NO:653), LFTLDEKN(SEQ ID NO:654), LFTLDEKNG (SEQ ID NO:655), NEK, NEKT (SEQ ID NO:656),NEKTG (SEQ ID NO:657), INEK (SEQ ID NO:658), INEKT (SEQ ID NO:659),INEKTG (SEQ ID NO:660), LINEK (SEQ ID NO:661), LINEKT (SEQ ID NO:662),LINEKTG (SEQ ID NO:663), FLINEK (SEQ ID NO:664), FLINEKT (SEQ IDNO:665), FLINEKTG (SEQ ID NO:666), KFLINEK (SEQ ID NO:667), KFLINEKT(SEQ ID NO:668) and KFLINEKTG (SEQ ID NO:4052); or (b) an analogue ofany of the foregoing sequences that differs in one or moresubstitutions, deletions, additions and/or insertions such that thatability of the analogue to modulate a cadherin-related neuronalreceptor-mediated function is not substantially diminished. For example,the agent may comprise a linear peptide having the sequenceN-Ac-KFHIDPVSG-NH₂ (SEQ ID NO:585), N-Ac-QFSIDADTG-NH₂ (SEQ ID NO:599),N-Ac-TFHIDSVSG-NH₂ (SEQ ID NO:613), N-Ac-AFNIDSNSG-NH₂ (SEQ ID NO:627),N-Ac-KFTIDSSSG-NH₂ (SEQ ID NO:641), N-Ac-LFTLDEKNG-NH₂ (SEQ ID NO:655)or N-Ac-KFLINEKTG-NH₂ (SEQ ID NO:4052). The cnr CAR sequence may, butneed not, be present within a cyclic peptide.

[0040] Any of the above modulating agents may, within certainembodiments, be linked to one or more of a drug, detectable marker,targeting agent or support material. Alternatively, or in addition, amodulating agent as described above, may further comprise one or moreof: (a) a CAR sequence that is specifically recognized by an adhesionmolecule other than the particular nonclassical cadherin; and/or (b) anantibody or antigen-binding fragment thereof that specifically binds toa CAR sequence that is specifically recognized by an adhesion moleculeother than the nonclassical cadherin. For example, such an adhesionmolecule may be a classical cadherin, integrin, occludin, claudin,N-CAM, fibronectin, laminin or other extracellular matrix protein. Inaddition, or alternatively, a modulating agent may comprise a CARsequence from a different non-classical cadherin, such that multiplenon-classical cadherin CAR sequences are linked together within themodulating agent.

[0041] Within other aspects, the present invention providespharmaceutical compositions comprising a modulating agent as describedabove in combination with a pharmaceutically acceptable carrier. Withinsuch compositions, the modulating agent may, but need not, be presentwithin a sustained-release formulation. Such compositions may, withincertain embodiments, further comprise a drug and/or a modulator of celladhesion that comprises one or more of: (a) a CAR sequence that isspecifically recognized by an adhesion molecule other than thenonclassical cadherin; and/or (b) an antibody or antigen-bindingfragment thereof that specifically binds to a CAR sequence that isspecifically recognized by an adhesion molecule other than thenonclassical cadherin.

[0042] The present invention further provides, within other aspects,methods for modulating one or more nonclassical cadherin-mediatedfunctions. Such methods generally comprise contacting a nonclassicalcadherin-expressing cell with a modulating agent as described above.Suitable cells include, but are not limited to, epithelial cells,endothelial cells, neural cells, tumor cells and lymphocytes. Withinsuch methods, the modulating agent may, but need not, be present withina pharmaceutical composition as recited above.

[0043] Within certain aspects, methods are provided for inhibitingadhesion of nonclassical cadherin-expressing cells in a mammal,comprising administering to a mammal a modulating agent as providedabove that inhibits cell adhesion mediated by the nonclassical cadherin.Such modulating agents should inhibit cell adhesion with an activitythat is not substantially diminished relative to the activity of thenonclassical cadherin in soluble form, within a cell adhesion assay suchas the assays provided herein.

[0044] Within further aspects, the present invention provides methodsfor enhancing the delivery of a drug through the skin of a mammal,comprising contacting epithelial cells of a mammal with a drug and amodulating agent as described above, wherein the step of contacting isperformed under conditions and for a time sufficient to allow passage ofthe drug across the epithelial cells, and wherein the modulating agentinhibits nonclassical cadherin-mediated cell adhesion. Such modulatingagents may pass into the blood stream of the mammal. Within certainembodiments, the modulating agent is linked to the drug. The step ofcontacting may, but need not, be performed via a skin patch comprisingthe modulating agent and the drug, and such skin patches are furtherprovided herein. Preferred modulating agents for use within such methodsare those that inhibit cell adhesion mediated by OB-cadherin,cadherin-5, a desmoglein and/or a desmocollin, as described herein.

[0045] Methods are further provided for facilitating blood sampling in amammal, comprising contacting epithelial cells of a mammal with amodulating agent as described above, wherein the modulating agentinhibits nonclassical cadherin-mediated cell adhesion, and wherein thestep of contacting is performed under conditions and for a timesufficient to allow passage of one or more blood components across theepithelial cells. Preferred modulating agents for use within suchmethods are those that inhibit cell adhesion mediated by OB-cadherin,cadherin-5, a desmoglein and/or a desmocollin, as described herein. Thestep of contacting may be performed via a skin patch comprising themodulating agent, and (optionally) a reagent for detecting a bloodcomponent of interest, and such kits are specifically provided herein.Within certain embodiments, the epithelial cells are skin cells or aregum cells.

[0046] Within further aspects, methods are provided for enhancing thedelivery of a drug to a tumor in a mammal, comprising administering to amammal a modulating agent as described above, wherein the modulatingagent inhibits nonclassical cadherin-mediated cell adhesion. Suitabletumors include, but are not limited to, bladder tumors, ovarian tumors,breast tumors, stomach tumors and kidney tumors, and the modulatingagent may be administered locally to the tumor or may be administeredsystemically. Preferred modulating agents for use within such methodsare those that inhibit cell adhesion mediated by OB-cadherin,cadherin-5, cadherin-6, a desmoglein and/or a desmocollin, as describedherein.

[0047] Within other aspects, the present invention provides methods fortreating cancer and/or inhibiting metastasis in a mammal, comprisingadministering to a mammal a modulating agent as described above, whereinthe modulating agent inhibits cadherin-mediated cell adhesion. Themammal may be afflicted with a cancer such as a carcinoma, leukemia ormelanoma, and the modulating agent may be administered to the tumor orsystemically. Preferred modulating agents for use within such methodsare those that inhibit cell adhesion mediated by OB-cadherin,cadherin-5, cadherin-6, a desmoglein and/or a desmocollin, as describedherein.

[0048] Within other aspects, methods are provided for inhibitingangiogenesis in a mammal, comprising administering to a mammal amodulating agent as described above, wherein the modulating agentinhibits nonclassical cadherin-mediated cell adhesion. Preferredmodulating agents for use within such methods are those that inhibitcell adhesion mediated by cadherin-5, as described herein.

[0049] The present invention further provides, within other aspects,methods for inducing apoptosis in a nonclassical cadherin-expressingcell, comprising contacting a nonclassical cadherin-expressing cell witha modulating agent as described above, wherein the modulating agentinhibits nonclassical cadherin-mediated cell adhesion.

[0050] In further aspects, methods are provided for preventing ortreating obesity in a mammal, comprising administering to a mammal amodulating agent as described above, wherein the modulating agentinhibits an OB-cadherin and/or cadherin-5 mediated function.

[0051] Methods are further provided for stimulating blood vesselregression, comprising administering to a mammal a modulating agent asdescribed above, wherein the modulating agent inhibits an OB-cadherinand/or cadherin-5 mediated function.

[0052] The present invention further provides, within other aspects,methods for enhancing drug delivery to the central nervous system of amammal, comprising administering to a mammal a modulating agent asdescribed above, wherein the modulating agent inhibits a nonclassicalcadherin-mediated function. Preferably, the modulating agent inhibits anOB-cadherin and/or cadherin-5 mediated function.

[0053] The present invention further provides, in other aspects, methodsfor enhancing and/or directing neurite outgrowth, comprising contactinga neuron with a modulating agent as described above, wherein themodulating agent enhances a nonclassical cadherin-mediated function.Preferably, the modulating agent enhances a function mediated bycadherin-7, cadherin-8, cadherin-12, cadherin-14, cadherin-15,T-cadherin, PB-cadherin, a protocadherin and/or a cnr.

[0054] Methods are also provided, within further aspects, for treating ademyelinating neurological disease such as multiple sclerosis in amammal, comprising administering to a mammal a modulating agent asdescribed above. Within certain embodiments, the modulating agent isadministered by implantation with Schwann cells, oligodendrocyteprogenitor cells and/or oligodendrocytes. Preferably, the modulatingagent enhances a function mediated by cadherin-7, cadherin-8,cadherin-12, cadherin-14, cadherin-15, T-cadherin, PB-cadherin, aprotocadherin and/or a cnr.

[0055] Methods are further provided for increasing vasopermeability in amammal, comprising administering to a mammal a modulating agent asdescribed above, wherein the modulating agent inhibits a nonclassicalcadherin-mediated function. Preferably, the modulating agent inhibitsOB-cadherin and/or cadherin-5 mediated cell adhesion.

[0056] Within other aspects, the present invention provides methods forenhancing adhesion of nonclassical cadherin-expressing cells, comprisingcontacting nonclassical cadherin-expressing cells with a modulatingagent as described above, wherein the modulating agent enhancesnonclassical cadherin-mediated cell adhesion, wherein the step ofcontacting is performed under conditions and for a time sufficient todetectably enhance adhesion of the cells. Within certain embodiments,modulating agents for use within such methods are linked to a supportmolecule or a solid support.

[0057] Within related aspects, the present invention provides methodsfor facilitating wound healing and/or reducing scar tissue in a mammal,comprising contacting a wound in a mammal with a modulating agent asdescribed above, wherein the modulating agent enhances cadherin-mediatedcell adhesion. Preferably, the modulating agent enhances OB-cadherin,cadherin-5, desmoglein and/or desmocollin mediated cell adhesion. Withincertain embodiments, modulating agents for use within such methods arelinked to a support molecules or a solid support.

[0058] Methods are also provided, within other aspects, for enhancingadhesion of foreign tissue implanted within a mammal, comprisingcontacting a site of implantation of foreign tissue in a mammal with amodulating agent as described above, wherein the modulating agentenhances nonclassical cadherin-mediated cell adhesion. Such foreigntissue may be a skin graft or organ implant. Within certain embodiments,the modulating agent is linked to a support material. Preferably, themodulating agent enhances OB-cadherin, cadherin-5, desmoglein and/ordesmocollin mediated cell adhesion. Within certain embodiments,modulating agents for use within such methods are linked to a supportmolecules or a solid support.

[0059] Within further aspects, the present invention provides methodsfor inhibiting synaptic stability in a mammal, comprising administeringto a mammal a modulating agent as described above, wherein themodulating agent inhibits a cnr-mediated function.

[0060] Within further aspects, methods are provided for modulating theimmune system of a mammal, comprising administering to a mammal amodulating agent as described above, wherein the modulating agentinhibits a nonclassical cadherin-mediated function. Preferably, themodulating agent inhibits OB-cadherin, cadherin-5, cadherin-6 and/orcadherin-8 mediated cell adhesion.

[0061] Within other aspects, the present invention provides methods forpreventing pregnancy in a mammal, comprising administering to a mammal amodulating agent as described above, wherein the modulating agentinhibits a nonclassical cadherin-mediated function. Preferably, themodulating agent inhibits OB-cadherin or cadherin-5 mediated celladhesion.

[0062] The present invention further provides methods for detecting thepresence of nonclassical cadherin-expressing cells in a sample,comprising: (a) contacting a sample with an antibody or antigen-bindingfragment thereof that binds to a nonclassical CAR sequence as describedabove under conditions and for a time sufficient to allow formation ofan antibody-cadherin complex; and (b) detecting the level ofantibody-cadherin complex, and therefrom detecting the presence ofnonclassical cadherin expressing cells in a sample. The antibody may belinked to a support material or a detectable marker such as afluorescent marker. In certain embodiments, the step of detecting isperformed using fluorescence activated cell sorting.

[0063] Kits for detecting the presence of cadherin-expressing cells in asample are also provided. Such kits may comprise: (a) an antibody orantigen-binding fragment thereof that specifically binds to anonclassical cadherin CAR sequence; and (b) a detection reagent.

[0064] Within other aspects, the present invention provides methods foridentifying a compound capable of modulating a nonclassicalcadherin-mediated function, comprising: (a) contacting an antibody orantigen-binding fragment thereof that specifically binds to anonclassical cadherin CAR sequence as described above with a testcompound; and (b) detecting the level of antibody or fragment that bindsto the test compound, and therefrom identifying a compound capable ofmodulating cadherin-mediated cell adhesion.

[0065] These and other aspects of the present invention will becomeapparent upon reference to the following detailed description andattached drawings. All references disclosed herein are herebyincorporated by reference in their entirety as if each was incorporatedindividually.

BRIEF DESCRIPTION OF THE DRAWINGS

[0066] FIGS. 1A-1AA are diagrams depicting the structure of classical(FIG. 1A) and nonclassical (FIGS. 1B to 1AA) cadherins. Theextracellular domains are designated EC1-EC5 for most cadherins; EC1-EC7for LI-cadherin and EC1-EC6 for protocadherins and cnr. The hydrophobicdomain that transverses the plasma membrane (PM) is represented by TM,and the varying number of cytoplasmic domains are represented by CP. Thecalcium binding motifs for classical cadherins are shown in FIG. 1A byDXNDN (SEQ ID NO:1), DXD and LDRE (SEQ ID NO:2), and the calcium bindingmotifs for other cadherins are also indicated above the extracellulardomains. Below the extracellular domains, the nine amino acid CARsequences are shown (SEQ ID NOS: 85, 99, 113, 127, 141, 154, 168, 182,198, 210, 224, 238, 252, 266, 280, 294, 308, 319, 333, 347, 361, 375,389, 403, 417, 431, 445, 459, 473, 489, 503, 517, 531, 545, 559, 571,585, 599, 613, 627, 641, 655 and 4052).

[0067]FIG. 2 provides the amino acid sequences of representativemammalian nonclassical cadherin extracellular domains, as indicated (SEQID NOs 4-43). Calcium binding motifs are shown in bold, andrepresentative CAR sequences are shown in bold and underlined.

[0068]FIG. 3 provides the amino acid sequences of representativemammalian OB-cadherin EC1 domains: human OB-cadherin (SEQ ID NO:44) andmouse OB-cadherin (SEQ ID NO:45).

[0069] FIGS. 4A-4C provide structures of representative modulatingagents (SEQ ID NOS: 85, 669-674, 676, 677, 683, 697, 704 and 717).

[0070] FIGS. 5A-5C are photographs showing cultures of human breastcancer cells in the presence (FIGS. 5B and 5C) and absence (FIG. 5A) ofa representative linear peptide modulating agent. FIG. 5A shows thecells 24 hours after exposure to 100 μl water/1 ml culture medium(magnification 200×). FIGS. 5B and 5C show the cells 24 hours afterexposure to 100 μL of a solution containing 10 mg/mL N-Ac-IFVIDDKSG-NH₂(SEQ ID NO:85) per 1 mL culture medium (magnifications of 200× and 100×,respectively). Arrows indicate rounded cells.

[0071] FIGS. 6A-6F are photographs showing human umbilical veinendothelial cells in the presence (FIGS. 6E and 6F) and absence (FIGS.6A and 6B) of 75 μg/mL of a representative linear peptide modulatingagent N-Ac-VFRVDAETGD-NH₂ (SEQ ID NO:64). FIGS. 6C and 6D show the cellsin the presence of 75 μg/mL of a similar peptide without the terminalfunctional groups. Cells were incubated with peptide for 60 minutes,fixed and immunolabeled with monoclonal antibodies directed againstVE-cadherin, and were observed at 400× (A, C and E) and 1000× (B, D andF).

[0072] FIGS. 7A-7F provide further structures of representativemodulating agents (SEQ ID NOS: 736, 823, 910, 983, 1050, 1064, 1079,1303, 1373, 1388, 1589, 1649, 1736, 1797, 1884, 1945, 1958, 2092, 2153,2240, 2300, 2333, 2629, 2716, 2746, 2731, 3066, 3081, 3096, 3327, 3342,3572, 3587, 3602, 3617, 3633, 3648, 3663, 4039, 4045).

DETAILED DESCRIPTION OF THE INVENTION

[0073] As noted above, the present invention provides methods formodulating cadherin-mediated functions, such as cell adhesion. Thepresent invention is based upon the identification of previously unknowncell adhesion recognition (CAR) sequences present in nonclassicalcadherins. A modulating agent may generally comprise one or morenonclassical cadherin CAR sequences (or analogues or mimetics thereof),with or without one or more additional CAR sequences, as describedbelow. Peptide CAR sequences may be present within a linear or cyclicpeptide. Alternatively, or in addition, a modulating agent may comprisea polynucleotide encoding a peptide comprising one or more nonclassicalcadherin CAR sequences and/or a modulating agent may comprise asubstance (such as an antibody or antigen-binding fragment thereof) thatspecifically binds to a nonclassical cadherin CAR sequence.

[0074] In general, to modulate a nonclassical cadherin-mediatedfunction, a cell that expresses a nonclassical cadherin is contactedwith a modulating agent either in vivo or in vitro. Within certainaspects, the methods provided herein inhibit a nonclassicalcadherin-mediated function. Such methods include, for example, methodsfor treating diseases or other conditions characterized by undesirablecell adhesion or for facilitating drug delivery to a specific tissue ortumor. Certain methods may inhibit cell adhesion (e.g., cancer celladhesion), as well as cancer invasion and metastasis. Alternatively, amodulating agent may, such as when linked to a matrix or to anothermodulating agent via a linker, be used to enhance a nonclassicalcadherin-mediated function, such as cell adhesion. Such conjugates maybe used, for example, to facilitate wound healing or the adhesion ofimplants.

Modulating Agents

[0075] As noted above, the term “modulating agent,” as used herein,refers to a molecule comprising at least one of the followingcomponents:

[0076] (a) a linear or cyclic peptide sequence that is at least 50%identical to a nonclassical cadherin CAR sequence (i.e., a nonclassicalcadherin CAR sequence or an analogue thereof that retains at least 50%sequence identity);

[0077] (b) a mimetic (e.g., peptidomimetic or small molecule mimic) of anonclassical cadherin CAR sequence;

[0078] (c) a substance, such as an antibody or antigen-binding fragmentthereof, that specifically binds a nonclassical cadherin CAR sequence;and/or

[0079] (d) a polynucleotide encoding a polypeptide that comprises anonclassical cadherin CAR sequence or analogue thereof.

[0080] A modulating agent may consist entirely of one or more of theabove elements, or may additionally comprise further peptide and/ornon-peptide regions. Additional peptide regions may be derived from anonclassical cadherin (preferably an extracellular domain that comprisesa CAR sequence) and/or may be heterologous. Within certain preferredembodiments, a modulating agent contains no more than 85 consecutiveamino acid residues, and preferably no more than 50 consecutive aminoacid residues, present within a nonclassical cadherin.

[0081] A modulating agent is further capable of modulating a functionmediated by a nonclassical cadherin. Such activity may generally beassessed using, for example, representative assays provided herein.Certain modulating agents inhibit an interaction between nonclassicalcadherin molecules and/or between a nonclassical cadherin and adifferent adhesion molecule. For functions (e.g., cell adhesion) thatare inhibited by a full length nonclassical cadherin, such a modulatingagent may inhibit the function with an activity that is notsubstantially diminished relative to the full length nonclassicalcadherin (i.e., the modulating agent inhibits the function at least aswell as soluble cadherin, when contacted with cells that express thecadherin). For example, a modulating agent may be as effective assoluble cadherin in preventing and/or disrupting adhesion ofcadherin-expressing cells. Alternatively, to enhance adhesion ofnonclassical cadherin-expressing cells, a modulating agent may comprisean antibody or antigen-binding fragment thereof and/or multiple peptidesor mimetics linked to a support material. Such modulating agents mayfunction as a biological glue to bind nonclassical cadherin-expressingcells, and should result in a detectable enhancement of cell adhesion(preferably an enhancement that is at least as great as that observedfor immobilized cadherin or antibody directed against the cadherin).

[0082] The term “nonclassical cadherin,” as used herein, refers to apolypeptide that contains characteristic cadherin repeats, but does notcontain an HAV CAR sequence. As used herein, a “cadherin repeat” refersto an amino acid sequence that is approximately 110 amino acid residuesin length (generally 100 to 120 residues, preferably 105 to 115residues), comprises an extracellular domain, and contains three calciumbinding motifs (DXD, XDXE and DXXDX; SEQ ID NOS: 46 and 47 respectively)in the same order and in approximately the same position (see, e.g.,FIG. 2). The presence of an extracellular domain may generally bedetermined using well known techniques, such as the presence of one ormore of: a hydrophilic sequence, a region that is recognized by anantibody, a region that is cleaved by trypsin and/or a potentialglycosylation site with the glycosylation motif Asn-X-Ser/Thr. Thesecond calcium binding motif commonly has the sequence LDRE, althoughvariants of this sequence with conservative substitutions are alsoobserved, including MDRE (SEQ ID NO:65), LDFE (SEQ ID NO:66), LDYE (SEQID NO:67), IDRE (SEQ ID NO:68), VDRE (SEQ ID NO:69) and IDFE (SEQ IDNO:70). Within most cadherin repeats, the third calcium binding motifhas the sequence [L,I,V]-X-[L,I,V]-X-D-X—N-D-[N,H]-X—P (SEQ ID NO: 72),wherein residues indicated in brackets may be any one of the recitedresidues. A preferred third calcium binding motif has the sequence DXNDN(SEQ ID NO:1), although one or both of the D residues may be replaced byan E. Homology among cadherin repeats is generally at least 20%,preferably at least 30%, as determined by the ALIGN algorithm (Myers andMiller, CABIOS 4:11-17, 1988). Most cadherins comprise at least fivecadherin repeats, along with a hydrophobic domain that transverses theplasma membrane and, optionally, one or more cytoplasmic domains, asshown in FIGS. 1B-1AA. Occasionally, however, a cadherin may substitutean extracellular domain that contains fewer than three calcium bindingmotifs for one or more of the cadherin repeats. For example, as shown inFIG. 2, the second extracellular domain of LI-cadherin comprises onlythe first calcium binding motif (DXD).

[0083] As noted above, a typical, or type II, cadherins includecadherin-5 (VE-cadherin), cadherin-6 (K-cadherin), cadherin-7,cadherin-8, cadherin-11 (OB-cadherin), cadherin-12, cadherin-14,cadherin-15 and PB-cadherin. Types III-X include LI-cadherin,T-cadherin, protocadherins (e.g., protocadherins 42, 43 and 68),desmocollins (e.g., desmocollins 1, 2, 3 and 4), desmogleins (e.g.,desmogleins 1 and 2), and cadherin-related neuronal receptors. Thesequence of various extracellular domains of each of these nonclassicalcadherins is shown in FIG. 2, and SEQ ID NOs: 4-43.

[0084] A nonclassical cadherin CAR sequence, as used herein, is an aminoacid sequence that is present within in a naturally occurringnonclassical cadherin and that is capable of detectably modulating anonclassical cadherin-mediated function, such as cell adhesion, asdescribed herein. In other words, contacting a nonclassicalcadherin-expressing cell with a peptide comprising a CAR sequenceresults in a detectable change in a nonclassical cadherin-mediatedfunction using at least one of the representative assays providedherein. CAR sequences are generally recognized in vivo by a nonclassicalcadherin or other adhesion molecule (i.e., a molecule that mediates celladhesion via a receptor on the cell surface), and are necessary formaximal heterophilic and/or homophilic interaction. CAR sequences may beof any length, but generally comprise at least three amino acidresidues, preferably 4-16 amino acid residues, and more preferably 5-9amino acid residues. A peptide modulating agent may comprise any numberof amino acid residues, but preferred agents comprise 3-50 residues,preferably 4-16 residues.

[0085] It has been found, within the context of the present invention,that certain nonclassical cadherin CAR sequences share the consensussequence: Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly(SEQ ID NO:3)

[0086] Within the consensus sequence, Aaa, Baa, Caa and Daa indicateindependently selected amino acid residues; “IIe/Leu/Val” indicates anamino acid that is isoleucine, leucine or valine; “Asp/Asn/Glu”indicates an amino acid that is aspartic acid, asparagine or glutamicacid; and “Ser/Thr/Asn” indicates an amino acid that is serine,threonine or asparagine. Representative nonclassical cadherin CARsequences are provided within Table I. CAR sequences specificallyprovided herein further include portions of such representative CARsequences, as well as longer polypeptides that comprise at least aportion of such sequences. Additional nonclassical cadherin CARsequences may be identified based on sequence homology to thenonclassical cadherin CAR sequences provided herein, and based on theability of a peptide comprising such a sequence to modulate anonclassical cadherin-mediated function within a representative assaydescribed herein. Within certain embodiments, a modulating agentcomprises at least three consecutive residues, preferably at least fiveconsecutive residues and more preferably at least seven consecutiveresidues, of a nonclassical cadherin CAR sequence that satisfies theabove consensus sequence. TABLE I Representative Nonclassical CadherinCAR Sequences Cadherin CAR Sequence Human OB-cadherin EC1 FFVIEEYTG (SEQID NO:99) Human OB-cadherin EC1 IFVIDDKSG (SEQ ID NO:85) HumanOB-cadherin EC2 YFSVEAQTG (SEQ ID NO:113) Human cadherin-5 EC1 VFRVDAETG(SEQ ID NO:127) Human cadherin-6 EC1 FFLLEEYTG (SEQ ID NO:154) Humancadherin-6 EC1 LFIINENTG (SEQ ID NO:141) Human cadherin-6 EC2 YFSVESETG(SEQ ID NO:168) Human cadherin-6 EC4 IFNIDSGNG (SEQ ID NO:182) Chickencadherin-7 EC1 IFIIDENTG (SEQ ID NO:196) Chicken cadherin-7 EC2YFSVEPKTG (SEQ ID NO:210) Chicken cadherin-7 EC4 YFNIDANSG (SEQ IDNO:224) Human cadherin-8 EC1 MFVLEEFSG (SEQ ID NO:252) Humancadherin-8EC1 TFQINDVTG (SEQ ID NO:238) Human cadherin-12 EC1 VFTIDETTG (SEQ IDNO:266) Human cadherin-12 EC2 YFSIDPKTG (SEQ ID NO:280) Humancadherin-14 EC1 IFIIDDTTG (SEQ ID NO:294) Human cadherin-14 EC2YFSVDPKTG (SEQ ID NO:308) Human cadherin-14 EC4 FFNIDANTG (SEQ IDNO:319) Human cadherin-15 EC1 VFSIDKFTG (SEQ ID NO:333) Humancadherin-15 EC2 LFSIDELTG (SEQ ID NO:347) Human T-cadherin EC1 IFRINENTG(SEQ ID NO:361) RatPB-cadherin EC1 FFVVEEYTG (SEQ ID NO:375) RatPB-cadherin EC2 HFTVDPKTG (SEQ ID NO:403) RatPB-cadherin EC4 IFDIDADTG(SEQ ID NO:417) Human Ll-cadherin EC2 YFQINNKTG (SEQ ID NO:431) Humanprotocadherin 43 LFALDLVTG (SEQ ID NO:445) EC3 Human protocadherin 43YFTINRDNG (SEQ ID NO:459) EC5 Human protocadherin 68 LFSIDPKTG (SEQ IDNO:473) EC3 Human protocadherin 68 LFEIDPSSG (SEQ ID NO:489) EC6 Humandesmogleini EC1 IFVINQKTG (SEQ ID NO:503) Human desmo leini EC2MFIINRNTG (SEQ ID NO:517) Human desmoglein2 EC2 VFYLNKDTG (SEQ IDNO:531) Human desmocollin 1 EC1 LFYIEKDTG (SEQ ID NO:545) Humandesmocollin 2 EC1 LFYVERDTG (SEQ ID NO:559) Human desmocollin 3/4LFYIERDTG (SEQ ID NO:571) EC1 Mouse Cnn EC3 KFHIDPVSG (SEQ ID NO:585)Mouse Cnr2 EC3 QFSIDADTG (SEQ ID NO:599) Mouse Cnr3 EC3 TFHIDSVSG (SEQID NO:613) Mouse Cnr5 EC3 AFNIDSNSG (SEQ ID NO:627) Mouse Cnr6 EC3KFTIDSSSG (SEQ ID NO:641) Mouse Cnr7 EC3 LFTLDEKNG (SEQ ID NO:655) MouseCnr8 EC3 KFLINEKTG (SEQ ID NO:4052) CONSENSUS xFxidxxtG (SEQ ID NO:3) len v n  s l e  n

[0087] Nonclassical cadherin CAR sequences are generally physicallylocated within the cadherin molecule in or near the binding site of anadhesion molecule (i.e., within 10 amino acids, and preferably within 5amino acids). The location of a binding site may generally be determinedusing well known techniques, such as evaluating the ability of a portionof the nonclassical cadherin to bind to the same nonclassical cadherinor to another adhesion molecule. Any standard binding assay may beemployed for such an evaluation. Recognition of a CAR sequence by thenonclassical cadherin or other adhesion molecule results in a measurableeffect on an adhesion molecule function, such as cell adhesion. Peptidescomprising a CAR sequence generally inhibit such a function unlesslinked, as described herein, to form an enhancer of adhesion moleculefunction.

[0088] Certain preferred nonclassical cadherin CAR sequences comprise3-9 amino acid residues of a sequence provided in Table I. For example,a CAR sequence may comprise 3, 4 or 5 residues of a 9 amino acidsequence in Table I. For example, an OB cadherin CAR sequence generallycomprises at least the sequence EEY, DDK or EAQ. Within certainembodiments, a CAR sequence may include at least residues 5-7 of asequence in Table I.

[0089] Representative OB-cadherin CAR sequences comprise one or more ofthe peptide sequences DDK, IDDK (SEQ ID NO:4051) DDKS (SEQ ID NO:73),VIDDK (SEQ ID NO:74), IDDKS (SEQ ID NO:75), VIDDKS (SEQ ID NO:76), DDKSG(SEQ ID NO:77), IDDKSG (SEQ ID NO:78), VIDDKSG (SEQ ID NO:79), FVIDDK(SEQ ID NO:80), FVIDDKS (SEQ ID NO:81), FVIDDKSG (SEQ ID NO:82), IFVIDDK(SEQ ID NO:83), FVIDDKS (SEQ ID NO:84), IFVIDDKSG (SEQ ID NO:85), EEY,IEEY (SEQ ID NO:86), EEYT (SEQ ID NO:87), VIEEY (SEQ ID NO:88), IEEYT(SEQ ID NO:89), VIEEYT (SEQ ID NO:90), EEYTG (SEQ ID NO:91), IEEYTG (SEQID NO:92), VIEEYTG (SEQ ID NO:93), FVIEEY (SEQ ID NO:94), FVIEEYT (SEQID NO:95), FVIEEYTG (SEQ ID NO:96), FFVIEEY (SEQ ID NO:97), FFVIEEYT(SEQ ID NO:98), FFVIEEYTG (SEQ ID NO:99), EAQ, VEAQ (SEQ ID NO:100),EAQT (SEQ ID NO:101), SVEAQ (SEQ ID NO:102), VEAQT (SEQ ID NO:103),SVEAQT (SEQ ID NO:104), EAQTG (SEQ ID NO:105), VEAQTG (SEQ ID NO:106),SVEAQTG (SEQ ID NO:107), FSVEAQ (SEQ ID NO:108), FSVEAQT (SEQ IDNO:109), FSVEAQTG (SEQ ID NO:110), YFSVEAQ (SEQ ID NO: 111), YFSVEAQT(SEQ ID NO: 112) or YFSVEAQTG (SEQ ID NO:113). Linear peptides havingsuch sequences may be modified at the N- and/or C-termini, as in thepeptides N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85), N-Ac-FFVIEEYTG-NH₂ (SEQ IDNO:99) and N-Ac-YFSVEAQTG-NH₂ (SEQ ID NO:113).

[0090] Certain cadherin-5 CAR sequences comprise, for example, one ormore of the peptide sequences: DAE, VDAE (SEQ ID NO:114), DAET (SEQ IDNO:115), RVDAE (SEQ ID NO:116), VDAET (SEQ ID NO:117), RVDAET (SEQ IDNO:118), DAETG (SEQ ID NO:119), VDAETG (SEQ ID NO:120), RVDAETG (SEQ IDNO:121), FRVDAE (SEQ ID NO:122), FRVDAET (SEQ ID NO:123), FRVDAETG (SEQID NO:124), VFRVDAE (SEQ ID NO:125), VFRVDAET (SEQ ID NO:126) orVFRVDAETG (SEQ ID NO:127). Linear peptides having such sequences may bemodified at the N- and/or C-termini, as in the peptideN-Ac-VFRVDAETG-NH₂ (SEQ ID NO:127).

[0091] A cadherin-6 CAR sequence may comprise one or more of thesequences: NEN, INEN (SEQ ID NO128), NENT (SEQ ID NO:129), IINEN (SEQ IDNO:130), INENT (SEQ ID NO:131), IINENT (SEQ ID NO:132), NENTG (SEQ IDNO:133), INENTG (SEQ ID NO:134), IINENTG (SEQ ID NO:135), FIINEN (SEQ IDNO:136), FIINENT (SEQ ID NO:137), FIINENTG (SEQ ID NO:138), LFIINEN (SEQID NO:139), LFIINENT (SEQ ID NO:140), LFIINENTG (SEQ ID NO:141), EEY,EEYT (SEQ ID NO:142), EEYTG (SEQ ID NO:143), LEEY (SEQ ID NO:144), LEEYT(SEQ ID NO:145), LEEYTG (SEQ ID NO:146), LLEEY (SEQ ID NO:147), LLEEYTG(SEQ ID NO:148), FLLEEY (SEQ ID NO:149), FLLEEYT (SEQ ID NO:150),FLLEEYTG (SEQ ID NO:151), FFLLEEY (SEQ ID NO:152), FFLLEEYT (SEQ IDNO:153), FFLLEEYTG (SEQ ID NO:154), ESE, ESET (SEQ ID NO:155), ESETG(SEQ ID NO:156), VESE (SEQ ID NO:157), VSEST (SEQ ID NO:158), VESETG(SEQ ID NO:159), SVESE (SEQ ID NO:160), SVESET (SEQ ID NO:161), SVESETG(SEQ ID NO:162), FSVESE (SEQ ID NO:163), FSVESET (SEQ ID NO:164),FSVESETG (SEQ ID NO:165), YFSVESE (SEQ ID NO:166), YFSVESET (SEQ IDNO:167), YFSVESETG (SEQ ID NO:168), DSG, DSGN (SEQ ID NO:169), DSGNG(SEQ ID NO:170), IDSG (SEQ ID NO:171), IDSGN (SEQ ID NO:172), IDSGNG(SEQ ID NO:173), NIDSG (SEQ ID NO:174), NIDSGN (SEQ ID NO:175), NIDSGNG(SEQ ID NO:176), FNIDSG (SEQ ID NO:177), FNIDSGN (SEQ ID NO:178),FNIDSGNG (SEQ ID NO:179), IFNIDSG (SEQ ID NO:180), IFNIDSGN (SEQ IDNO:181) or IFNIDSGNG (SEQ ID NO:182). Linear peptides having suchsequences may be modified at the N- and/or C-termini, as in the peptidesN-Ac-FFLLEEYTG-NH₂ (SEQ ID NO:154), N-Ac-LFIINENTG-NH₂ (SEQ IDNO:141),N-Ac-YFSVESETG-NH₂ (SEQ ID NO:168) and N-Ac-IFNIDSGNG-NH₂ (SEQID NO:182).

[0092] A cadherin-7 CAR sequence may comprise, for example, one or moreof the sequences: DEN, IDEN (SEQ ID NO:183), DENT (SEQ ID NO:184), IIDEN(SEQ ID NO:185), IDENT (SEQ ID NO:186), IIDENT (SEQ ID NO:187), DENTG(SEQ ID NO:188), IDENTG (SEQ ID NO:189), IIDENTG (SEQ ID NO:190), FIIDEN(SEQ ID NO:191), FIIDENT (SEQ ID NO:192), FIIDENTG (SEQ ID NO:193),IFIIDEN (SEQ ID NO:194), IFIIDENT (SEQ ID NO:195), IFIIDENTG (SEQ IDNO:196), EPK, EPKT (SEQ ID NO:197), EPKTG (SEQ ID NO:198), VEPK (SEQ IDNO:199), VEPKT (SEQ ID NO:200), VEPKTG (SEQ ID NO:201), SVEPK (SEQ IDNO:202), SVEPKT (SEQ ID NO:203), SVEPKTG (SEQ ID NO:204), FSVEPK (SEQ IDNO:205), FSVEPKT (SEQ ID NO:206), FSVEPKTG (SEQ ID NO:207), YFSVEPK (SEQID NO:208), YFSVEPKT (SEQ ID NO:209), YFSVEPKTG (SEQ ID NO:210), DAN,DANS (SEQ ID NO:211), DANSG (SEQ ID NO:212), IDAN (SEQ ID NO:213), IDANS(SEQ ID NO:214), IDANSG (SEQ ID NO:215), NIDAN (SEQ ID NO:216), NIDANS(SEQ ID NO:217), NIDANSG (SEQ ID NO:218), FNIDAN (SEQ ID NO:219),FNIDANS (SEQ ID NO:220), FNIDANSG (SEQ ID NO:221), YFNIDAN (SEQ IDNO:222), YFNIDANS (SEQ ID NO:223) or YFNIDANSG (SEQ ID NO:224). Linearpeptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-IFIIDENTG-NH₂ (SEQ ID NO:196),N-Ac-YFSVEPKTG-NH₂ (SEQ ID NO:210) and N-Ac-YFNIDANSG-NH₂ (SEQ IDNO:224).

[0093] A cadherin-8 CAR sequence may comprise, for example, one or moreof the sequences: NDV, INDV (SEQ ID NO:225), NDVT (SEQ ID NO:226), QINDV(SEQ. ID NO:227), INDVT (SEQ ID NO:228), QINDVT (SEQ ID NO:229), NDVTG(SEQ ID NO:230), INDVTG (SEQ ID NO:231), QINDVTG (SEQ ID NO:232), FQINDV(SEQ ID NO:233), FQINDVT (SEQ ID NO:234), FQINDVTG (SEQ ID NO:235),IFQINDV (SEQ ID NO:236), IFQINDVT (SEQ ID NO:237), IFQINDVTG (SEQ IDNO:238), EEF, EEFS (SEQ ID NO:239), EEFSG (SEQ ID NO:240), LEEF (SEQ IDNO:241), LEEFS (SEQ ID NO:242), LEEFSG (SEQ ID NO:243), VLEEF (SEQ IDNO:244), VLEEFS (SEQ ID NO:245), VLEEFSG (SEQ ID NO:247), FVLEEF (SEQ IDNO:247), FVLEEFS (SEQ ID NO:248), FVLEEFSG (SEQ ID NO:249), MFVLEEF (SEQID NO:250), MFVLEEFS (SEQ ID NO:251) or MFVLEEFSG (SEQ ID NO:252).Linear peptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-MFVLEEFSG-NH₂ (SEQ ID NO:252) andN-Ac-IFQINDVTG-NH₂ (SEQ ID NO:238).

[0094] A cadherin-12 CAR sequence may comprise, for example, one or moreof the sequences: DET, IDET (SEQ ID NO:253), DETT (SEQ ID NO:254), TIDET(SEQ ID NO:255), IDETT (SEQ ID NO:256), TIDETT (SEQ ID NO:257), DETTG(SEQ ID NO:258), IDETTG (SEQ ID NO:259), TIDETTG (SEQ ID NO:260), FTIDET(SEQ ID NO:261), FTIDETT (SEQ ID NO:262), FTIDETTG (SEQ ID NO:263),VFTIDET (SEQ ID NO:264), VFTIDETT (SEQ ID NO:265), VFTIDETTG (SEQ IDNO:266), DPK, DPKT (SEQ ID NO:267), DPKTG (SEQ ID NO:268), IDPK (SEQ IDNO:269), IDPKT (SEQ ID NO:270), IDPKTG (SEQ ID NO:271), SIDPK (SEQ IDNO:272), SIDPKT (SEQ ID NO:273), SIDPKTG (SEQ ID NO:274), FSIDPK (SEQ IDNO:275), FSIDPKT (SEQ ID NO:276), FSIDPKTG (SEQ ID NO:277), YFSIDPK (SEQID NO:278), YFSIDPKT (SEQ ID NO:279) or YFSIDPKTG (SEQ ID NO:280).Linear peptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-VFTIDETTG-NH₂ (SEQ ID NO:266) andN-Ac-YFSIDPKTG-NH₂ (SEQ ID NO:280).

[0095] A cadherin-14 CAR sequence may comprise, for example, one or moreof the sequences: DDT, IDDT (SEQ ID NO:281), DDTT (SEQ ID NO:282), IIDDT(SEQ ID NO:283), IDDTT (SEQ ID NO:284), IIDDTT (SEQ ID NO:285), DDTTG(SEQ ID NO:286), IDDTTG (SEQ ID NO:287), IIDDTTG (SEQ ID NO:288), FIIDDT(SEQ ID NO:289), FIIDDTT (SEQ ID NO:290), FIIDDTTG (SEQ ID NO:291),IFIIDDT (SEQ ID NO:292), IFIIDDTT (SEQ ID NO:293), IFIIDDTTG (SEQ IDNO:294), DPK, DPKT (SEQ ID NO:295), DPKTG (SEQ ID NO:296), VDPK (SEQ IDNO:297), VDPKT (SEQ ID NO:298), VDPKTG (SEQ ID NO:299), SVDPK (SEQ IDNO:300), SVDPKT (SEQ ID NO:301), SVDPKTG (SEQ ID NO:302), FSVDPK (SEQ IDNO:303), FSVDPKT (SEQ ID NO:304), FSVDPKTG (SEQ ID NO:305), YFSVDPK (SEQID NO:306), YFSVDPKT (SEQ ID NO:307), YFSVDPKTG (SEQ ID NO:308), DAN,DANT (SEQ ID NO:309), DANTG (SEQ ID NO:310), IDANT (SEQ ID NO:311),IDANTG (SEQ ID NO:312), NIDANT (SEQ ID NO:313), NIDANTG (SEQ ID NO:314),FNIDANT (SEQ ID NO:315), FNIDANTG (SEQ ID NO:316), FFNIDAN (SEQ IDNO:317), FFNIDANT (SEQ ID NO:318) or FFNIDANTG (SEQ ID NO:319). Linearpeptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-IFIIDDTTG-NH₂ (SEQ ID NO:294),N-Ac-YFSVDPKTG-NH₂ (SEQ ID NO:308) and N-Ac-FFNIDANTG-NH₂ (SEQ IDNO:319).

[0096] A cadherin-15 CAR sequence may comprise, for example, one or moreof the sequences: DKF, IDKF (SEQ ID NO:320), DKFT (SEQ ID NO:321), SIDKF(SEQ ID NO:322), IDKFT (SEQ ID NO:323), SIDKFT (SEQ ID NO:324), DKFTG(SEQ ID NO:325), IDKFTG (SEQ ID NO:326), SIDKFTG (SEQ ID NO:327), FSIDKF(SEQ ID NO:328), FSIDKFT (SEQ ID NO:329), FSIDKFTG (SEQ ID NO:330),VFSIDKF (SEQ ID NO:331), VFSIDKFT (SEQ ID NO:332), VFSIDKFTG (SEQ IDNO:333), DEL, DELT (SEQ ID NO:334), DELTG (SEQ ID NO:335), IDEL (SEQ IDNO:336), IDELT (SEQ ID NO:337), IDELTG (SEQ ID NO:338), SIDEL (SEQ IDNO:339), SIDELT (SEQ ID NO:340), SIDELTG (SEQ ID NO:341), FSIDEL (SEQ IDNO:342), FSIDELT (SEQ ID NO:343), FSIDELTG (SEQ ID NO:344), LFSIDEL (SEQID NO:345), LFSIDELT (SEQ ID NO:346) or LFSIDELTG (SEQ ID NO:347).Linear peptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-VFSIDKFTG-NH₂ (SEQ ID NO:333) andN-Ac-LFSIDELTG-NH₂ (SEQ ID NO:347).

[0097] A T-cadherin CAR sequence may comprise, for example, one or moreof the sequences: NEN, INEN (SEQ ID NO:348), NENT (SEQ ID NO:349), RINEN(SEQ ID NO:350), INENT (SEQ ID NO:351), RINENT (SEQ ID NO:352), NENTG(SEQ ID NO:353), INENTG (SEQ ID NO:354), RINENTG (SEQ ID NO:355), FRINEN(SEQ ID NO:356), FRINENT (SEQ ID NO:357), FRINENTG (SEQ ID NO:358),IFRINEN (SEQ ID NO:359), IFRINENT (SEQ ID NO:360) or IFRINENTG (SEQ IDNO:361). Linear peptides having such sequences may be modified at the N-and/or C-termini, as in the peptide N-Ac-IFRINENTG-NH₂ (SEQ ID NO:361).

[0098] A PB-cadherin CAR sequence may comprise, for example, one or moreof the sequences: EEY, EEYT (SEQ ID NO:362), EEYTG (SEQ ID NO:363), VEEY(SEQ ID NO:364), VEEYT (SEQ ID NO:365), VEEYTG (SEQ ID NO:366), VVEEY(SEQ ID NO:367), VVEEYT (SEQ ID NO:368), VVEEYTG (SEQ ID NO:369), FVVEEY(SEQ ID NO:370), FVEEYT (SEQ ID NO:371), FVEEYTG (SEQ ID NO:372),FFVVEEY (SEQ ID NO:373), FFVVEEYT (SEQ ID NO:374), FFVVEEYTG (SEQ IDNO:375), DEL, DELT (SEQ ID NO:376), DELTG (SEQ ID NO:377), IDEL (SEQ IDNO:378), IDELT (SEQ ID NO:379), IDELTG (SEQ ID NO:380), LIDEL (SEQ IDNO:381), LIDELT (SEQ ID NO:382), LIDELTG (SEQ ID NO:383), FLIDEL (SEQ IDNO:384), FLIDELT (SEQ ID NO:385), FLIDELTG (SEQ ID NO:386), IFLIDEL (SEQID NO:387), IFLIDELT (SEQ ID NO:388), IFLIDELTG (SEQ ID NO:389), DPK,DPKT (SEQ ID NO:390), DPKTG (SEQ ID NO:391), VDPK (SEQ ID NO:392), VDPKT(SEQ ID NO:393), VDPKTG (SEQ ID NO:394), TVDPK (SEQ ID NO:395), TVDPKT(SEQ ID NO:396), TVDPKTG (SEQ ID NO:397), FTVDPK (SEQ ID NO:398),FTVDPKT (SEQ ID NO:399), FTVDPKTG (SEQ ID NO:400), HFTVDPK (SEQ IDNO:401), HFTVDPKT (SEQ ID NO:402), HFTVDPKTG (SEQ ID NO:403), DAD, DADT(SEQ ID NO:404), DADTG (SEQ ID NO:405), IDAD (SEQ ID NO:406), IDADT (SEQID NO:407), IDADTG (SEQ ID NO:408), DIDAD (SEQ ID NO:409), DIDADT (SEQID NO:410), DIDADTG (SEQ ID NO:411), FDIDAD (SEQ ID NO:412), FDIDADT(SEQ ID NO:413), FDIDADTG (SEQ ID NO:414), IFDIDAD (SEQ ID NO:415),IFDIDADT (SEQ ID NO:416) and IFDIDADTG (SEQ ID NO:417). Linear peptideshaving such sequences may be modified at the N- and/or C-termini, as inthe peptides N-Ac-FFVVEEYTG-NH₂ (SEQ ID NO:375), N-Ac-IFLIDELTG-NH₂ (SEQID NO:389), N-Ac-HFTVDPKTG-NH₂ (SEQ ID NO:403) and N-Ac-IFDIDADTG-NH₂(SEQ ID NO:417).

[0099] A LI-cadherin CAR sequence may comprise, for example, one or moreof the sequences: NNK, NNKT (SEQ ID NO:418), NNKTG (SEQ ID NO:419), INNK(SEQ ID NO:420), INNKT (SEQ ID NO:421), INNKTG (SEQ ID NO:422), QINNK(SEQ ID NO:423), QINNKT (SEQ ID NO:424), QINNKTG (SEQ ID NO:425), FQINNK(SEQ ID NO:426), FQINNKT (SEQ ID NO:427), FQINNKTG (SEQ ID NO:428),YFQINNK (SEQ ID NO:429), YFQINNKT (SEQ ID NO:430) or YFQINNKTG (SEQ IDNO:431). Linear peptides having such sequences may be modified at the N-and/or C-termini, as in the peptide N-Ac-YFQINNKTG-NH₂ (SEQ ID NO:431).

[0100] A protocadherin CAR sequence may comprise, for example, one ormore of the sequences: DLV, DLVT (SEQ ID NO:432), DLVTG (SEQ ID NO:433),LDLV (SEQ ID NO:434), LDLVT (SEQ ID NO:435), LDLVTG (SEQ ID NO:436),ALDLV (SEQ ID NO:437), ALDLVT (SEQ ID NO:438), ALDLVTG (SEQ ID NO:439),FALDLV (SEQ ID NO:440), FALDLVT (SEQ ID NO:441), FALDLVTG (SEQ IDNO:442), LFALDLV (SEQ ID NO:443), LFALDLVT (SEQ ID NO:444), LFALDLVTG(SEQ ID NO:445), NRD, NRDN (SEQ ID NO:446), NRDNG (SEQ ID NO:447), INRD(SEQ ID NO:448), INRDN (SEQ ID NO:449), INRDNG (SEQ ID NO:450), TINRD(SEQ ID NO:451), TINRDN (SEQ ID NO:452), TINRDNG (SEQ ID NO:453), FTINRD(SEQ ID NO:454), FTINRDN (SEQ ID NO:455), FTINRDNG (SEQ ID NO:456),YFTINRD (SEQ ID NO:457), YFTINRDN (SEQ ID NO:458), YFTINRDNG (SEQ IDNO:459), DPK, DPKT (SEQ ID NO:460), DPKTG (SEQ ID NO:461), IDPK (SEQ IDNO:462), IDPKT (SEQ ID NO:463), IDPKTG (SEQ ID NO:464), SIDPK (SEQ IDNO:465), SIDPKT (SEQ ID NO:466), SIDPKTG (SEQ ID NO:467), FSIDPK (SEQ IDNO:468), FSIDPKT (SEQ ID NO:469), FSIDPKTG (SEQ ID NO:470), LFSIDPK (SEQID NO:471), LFSIDPKT (SEQ ID NO:472), LFSIDPKTG (SEQ ID NO:473), DPS,DPSS (SEQ ID NO:474), DPSSG (SEQ ID NO:475), IDPS (SEQ ID NO:476), IDPSS(SEQ ID NO:477), IDPSSG (SEQ ID NO:478), EIDPS (SEQ ID NO:479), EIDPSS(SEQ ID NO:480), EIDPSSG (SEQ ID NO:481), FEIDPS (SEQ ID NO:482),FEIDPSS (SEQ ID NO:483), FEIDPS (SEQ ID NO:484), FEIDPSS (SEQ IDNO:485), FEIDPSSG (SEQ ID NO:486), LFEIDPS (SEQ ID NO:487), LFEIDPSS(SEQ ID NO:488) or LFEIDPSSG (SEQ ID NO:489). Linear peptides havingsuch sequences may be modified at the N- and/or C-termini, as in thepeptides N-Ac-LFALDLVTG-NH₂ (SEQ ID NO:445), N-Ac-YFTINRDNG-NH₂ (SEQ IDNO:459), N-Ac-LFSIDPKTG-NH₂ (SEQ ID NO:473) and N-Ac-LFEIDPSSG-NH₂ (SEQID NO:489).

[0101] A desmoglein CAR sequence may comprise, for example, one or moreof the sequences: NQK, NQKT (SEQ ID NO:490), NQKTG (SEQ ID NO:491), INQK(SEQ ID NO:492), INQKT (SEQ ID NO:493), INQKTG (SEQ ID NO:494), VINQK(SEQ ID NO:495), VINQKT (SEQ ID NO:496), VINQKTG (SEQ ID NO:497), FVINQK(SEQ ID NO:498), FVINQKT (SEQ ID NO:499), FVINQKTG (SEQ ID NO:500),IFVINQK (SEQ ID NO:501), IFVINQKT (SEQ ID NO:502), IFVINQKTG (SEQ IDNO:503), NRN, NRNT (SEQ ID NO:504), NRNTG (SEQ ID NO:505), INRN (SEQ IDNO:506), INRNT (SEQ ID NO:507), INRNTG (SEQ ID NO:508), IINRN (SEQ IDNO:509), IINRNT (SEQ ID NO:510), IINRNTG (SEQ ID NO:511), FIINRN (SEQ IDNO:512), FIINRNT (SEQ ID NO:513), FIINRNTG (SEQ ID NO:514), MFIINRN (SEQID NO:515), MFIINRNT (SEQ ID NO:516), MFIINRNTG (SEQ ID NO:517), NKD,NKDT (SEQ ID NO:518), NKDTG (SEQ ID NO:519), LNKD (SEQ ID NO:520), LNKDT(SEQ ID NO:521), LNKDTG (SEQ ID NO:522), YLNKD (SEQ ID NO:523), YLNKDT(SEQ ID NO:524), YLNKDTG (SEQ ID NO:525), FYLNKD (SEQ ID NO:526),FYLNKDT (SEQ ID NO:527), FYLNKDTG (SEQ ID NO:528), VFYLNKD (SEQ IDNO:529), VFYLNKDT (SEQ ID NO:530) or VFYLNKDTG (SEQ ID NO:531). Linearpeptides having such sequences may be modified at the N- and/orC-termini, as in the peptides N-Ac-IFVINQKTG-NH₂ (SEQ ID NO:503),N-Ac-MFIINRNTG-NH₂ (SEQ ID NO:517) and N-Ac-VFYLNKDTG-NH₂ (SEQ IDNO:531).

[0102] A desmocollin CAR sequence may comprise, for example, one or moreof the sequences EKD, EKDT (SEQ ID NO:532), EKDTG (SEQ ID NO:533), IEKD(SEQ ID NO:534), IEKDT (SEQ ID NO:535), IEKDTG (SEQ ID NO:536), YIEKD(SEQ ID NO:537), YIEKDT (SEQ ID NO:538), YIEKDTG (SEQ ID NO:539), FYIEKD(SEQ ID NO:540), FYIEKDT (SEQ ID NO:541), FYIEKDTG (SEQ ID NO:542),LFYIEKD (SEQ ID NO:543), LFYIEKDT (SEQ ID NO:544), LFYIEKDTG (SEQ IDNO:545), ERD, ERDT (SEQ ID NO:546), ERDTG (SEQ ID NO:547), VERD (SEQ IDNO:548), VERDT (SEQ ID NO:549), VERDTG (SEQ ID NO:550), YVERD (SEQ IDNO:551), YVERDT (SEQ ID NO:552), YVERDTG (SEQ ID NO:553), FYVERD (SEQ IDNO:554), FYVERDT (SEQ ID NO:555), FYVERDTG (SEQ ID NO:556), LFYVERD (SEQID NO:557), LFYVERDT (SEQ ID NO:558), LFYVERDTG (SEQ ID NO:559), IERD(SEQ ID NO:560), IERDT (SEQ ID NO:561), IERDTG (SEQ ID NO:562), YIERD(SEQ ID NO:563), YIERDT (SEQ ID NO:564), YIERDTG (SEQ ID NO:565), FYIERD(SEQ ID NO:566), FYIERDT (SEQ ID NO:567), FYIERDTG (SEQ ID NO:568),LFYIERD (SEQ ID NO:569), LFYIERDT (SEQ ID NO:570) or LFYIERDTG (SEQ IDNO:571). Linear peptides having such sequences may be modified at the N-and/or C-termini, as in the peptides N-Ac-LFYIEKDTG-NH₂ (SEQ ID NO:545),N-Ac-LFWERDTG-NH₂ (SEQ ID NO:559) and N-Ac-LFYIERDTG-NH₂ (SEQ IDNO:571).

[0103] A cadherin-related neuronal receptor (cnr) CAR sequence maycomprise, for example, one or more of the sequences: DPV, DPVS (SEQ IDNO:572), DPVSG (SEQ ID NO:573), IDPV (SEQ ID NO:574), IDPVS (SEQ IDNO:575), IDPVSG (SEQ ID NO:576), HIDPV (SEQ ID NO:577), HIDPVS (SEQ IDNO:578), HIDPVSG (SEQ ID NO:579), FHIDPV (SEQ ID NO:580), FHIDPVS (SEQID NO:581), FHIDPVSG (SEQ ID NO:582), KFHIDPV (SEQ ID NO:583), KFHIDPVS(SEQ ID NO:584), KFHIDPVSG (SEQ ID NO:585), DAD, DADT (SEQ ID NO:586),DADTG (SEQ ID NO:587), IDAD (SEQ ID NO:588), IDADT (SEQ ID NO:589),IDADTG (SEQ ID NO:590), SIDAD (SEQ ID NO:591), SIDADT (SEQ ID NO:592),SIDADTG (SEQ ID NO:593), FSIDAD (SEQ ID NO:594), FSIDADT (SEQ IDNO:595), FSIDADTG (SEQ ID NO:596), QFSIDAD (SEQ ID NO:597), QFSIDADT(SEQ ID NO:598), QFSIDADTG (SEQ ID NO:599), DSV, DSVS (SEQ ID NO:600),DSVSG (SEQ ID NO:601), IDSV (SEQ ID NO:602), IDSVS (SEQ ID NO:603),IDSVSG (SEQ ID NO:604), HIDSV (SEQ ID NO:605), HIDSVS (SEQ ID NO:606),HIDSVSG (SEQ ID NO:607), FHIDSV (SEQ ID NO:608), FHIDSVS (SEQ IDNO:609), FHIDSVSG (SEQ ID NO:610), TFHIDSV (SEQ ID NO:611), TFHIDSVS(SEQ ID NO:612), TFHIDSVSG (SEQ ID NO:613), DSN, DSNS (SEQ ID NO:614),DSNSG (SEQ ID NO:615), IDSN (SEQ ID NO:616), IDSNS (SEQ ID NO:617),IDSNSG (SEQ ID NO:618), NIDSN (SEQ ID NO:619), NIDSNS (SEQ ID NO:620),NIDSNSG (SEQ ID NO: 621), FNIDSN (SEQ ID NO: 622), FNIDSNS (SEQ IDNO:623), FNIDSNSG (SEQ ID NO:624), AFNIDSN (SEQ ID NO:625), AFNIDSNS(SEQ ID NO:626), AFNIDSNSG (SEQ ID NO:627), DSS, DSSS (SEQ ID NO:628),DSSSG (SEQ ID NO:629), IDSS (SEQ ID NO:630), IDSSS (SEQ ID NO:631),IDSSSG (SEQ ID NO:632), TIDSS (SEQ ID NO:633), TIDSSS (SEQ ID NO:634),TIDSSSG (SEQ ID NO:635), FTIDSS (SEQ ID NO:636), FTIDSSS (SEQ IDNO:637), FTIDSSSG (SEQ ID NO:638), KFTIDSS (SEQ ID NO:639), KFTIDSSS(SEQ ID NO:640), KFTIDSSSG (SEQ ID NO:641), DEK, DEKN (SEQ ID NO:642),DEKNG (SEQ ID NO:643), LDEK (SEQ ID NO:644), LDEKN (SEQ ID NO:645),LDEKNG (SEQ ID NO:646), TLDEK (SEQ ID NO:647), TLDEKN (SEQ ID NO:648),TLDEKNG (SEQ ID NO:649), FTLDEK (SEQ ID NO:650), FTLDEKN (SEQ IDNO:651), FTLDEKNG (SEQ ID NO:652), LFTLDEK (SEQ ID NO:653), LFTLDEKN(SEQ ID NO:654), LFTLDEKNG (SEQ ID NO:655), NEK, NEKT (SEQ ID NO:656),NEKTG (SEQ ID NO:657), INEK (SEQ ID NO:658), INEKT (SEQ ID NO:659),INEKTG (SEQ ID NO:660), LINEK (SEQ ID NO:661), LINEKT (SEQ ID NO:662),LINEKTG (SEQ ID NO:663), FLINEK (SEQ ID NO:664), FLINEKT (SEQ IDNO:665), FLINEKTG (SEQ ID NO:666), KFLINEK (SEQ ID NO:667), KFLINEKT(SEQ ID NO:668) or KFLINEKTG (SEQ ID NO:4052). Linear peptides havingsuch sequences may be modified at the N- and/or C-termini, as in thepeptides N-Ac-KFHIDPVSG-NH₂ (SEQ ID NO:585), N-Ac-QFSIDADTG-NH₂,(SEQ IDNO:599), N-Ac-TFHIDSVSG-NH₂ (SEQ ID NO:613), N-Ac-AFNIDSNSG-NH₂ (SEQ IDNO:627), N-Ac-KFTIDSSSG-NH₂ (SEQ ID NO:641), N-Ac-LFTLDEKNG-NH₂ (SEQ IDNO:655) and N-Ac-KFLINEKTG-NH₂ (SEQ ID NO:4052).

[0104] Those of ordinary skill in the art will recognize that similarpeptide sequences may be designed to modulate a function mediated byother cadherins, following identification of a CAR sequence as describedherein.

[0105] It will be apparent that certain of the peptide sequencesprovided above may modulate a function mediated by multiple nonclassicalcadherins. In general, peptides comprising a greater number ofconsecutive residues derived from a particular nonclassical cadherinhave a greater specificity for that cadherin. In addition, furtherflanking sequences may be included to enhance specificity. Such flankingsequences may be identified based on the sequences provided in FIG. 2,or based on published sequences. To achieve specificity (i.e.,modulation of a particular nonclassical cadherin function that isenhanced relative to the modulation of a function mediated by adifferent cadherin), the addition of 2 to 5 flanking residues(preferably at least one residue on either side of the CAR sequence) isgenerally sufficient. Specificity may be evaluated using assays for theability to inhibit functions mediated by particular cadherins, asdescribed herein.

[0106] As noted above, modulating agents as described herein maycomprise an analogue or mimetic of a nonclassical cadherin CAR sequence.An analogue generally retains at least 50% identity to a nativenonclassical cadherin CAR sequence, and modulates a nonclassicalcadherin-mediated function as described herein. Such analoguespreferably contain at least three consecutive residues of, and morepreferably at least five consecutive residues of, a nonclassicalcadherin CAR sequence. An analogue may contain any of a variety of aminoacid substitutions, additions, deletions and/or modifications (e.g.,side chain modifications). Preferred amino acid substitutions areconservative. A “conservative substitution” is one in which an aminoacid is substituted for another amino acid that has similar properties,such that one skilled in the art of peptide chemistry would expect thesecondary structure and hydropathic nature of the polypeptide to besubstantially unchanged. Amino acid substitutions may generally be madeon the basis of similarity in polarity, charge, solubility,hydrophobicity, hydrophilicity and/or the amphipathic nature of theresidues. For example, negatively charged amino acids include asparticacid and glutamic acid; positively charged amino acids include lysineand arginine; and amino acids with uncharged polar head groups havingsimilar hydrophilicity values include leucine, isoleucine and valine;glycine and alanine; asparagine and glutamine; and serine, threonine,phenylalanine and tyrosine. Other groups of amino acids that mayrepresent conservative changes include: (1) ala, pro, gly, glu, asp,gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala,phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. The criticaldetermining feature of a nonclassical cadherin CAR sequence analogue isthe ability to modulate a nonclassical cadherin-mediated function, whichmay be evaluated using the representative assays provided herein.

[0107] A mimetic is a non-peptidyl compound that is conformationallysimilar to a nonclassical cadherin CAR sequence, such that it modulatesa nonclassical cadherin-mediated function as described below. Suchmimetics may be designed based on techniques that evaluate the threedimensional structure of the peptide. For example, Nuclear MagneticResonance spectroscopy (NMR) and computational techniques may be used todetermine the conformation of a nonclassical cadherin CAR sequence. NMRis widely used for structural analyses of both peptidyl and non-peptidylcompounds. Nuclear Overhauser Enhancements (NOE's), coupling constantsand chemical shifts depend on the conformation of a compound. NOE dataprovides the interproton distance between protons through space and canbe used to calculate the lowest energy conformation for the nonclassicalcadherin CAR sequence. This information can then be used to designmimetics of the preferred conformation. Linear peptides in solutionexist in many conformations. By using conformational restrictiontechniques it is possible to fix the peptide in the active conformation.Conformational restriction can be achieved by i) introduction of analkyl group such as a methyl which sterically restricts free bondrotation; ii) introduction of unsaturation which fixes the relativepositions of the terminal and geminal substituents; and/or iii)cyclization, which fixes the relative positions of the sidechains.Mimetics may be synthesized where one or more of the amide linkages hasbeen replaced by isosteres, substituents or groups which have the samesize or volume such as —CH₂NH—, —CSNH—, —CH₂S—, —CH═CH—, —CH₂CH₂—,—CONMe- and others. These backbone amide linkages can also be part of aring structure (e.g., lactam). Mimetics may be designed where one ormore of the side chain functionalities of the nonclassical cadherin CARsequence are replaced by groups that do not necessarily have the samesize or volume, but have similar chemical and/or physical propertieswhich produce similar biological responses. Other mimetics may be smallmolecule mimics, which may be readily identified from small moleculelibraries, based on the three-dimensional structure of the CAR sequence.It should be understood that, within embodiments described below, ananalogue or mimetic may be substituted for a nonclassical cadherin CARsequence.

[0108] Modulating agents, or peptide portions thereof, may be linear orcyclic peptides. The term “cyclic peptide,” as used herein, refers to apeptide or salt thereof that comprises (1) an intramolecular covalentbond between two non-adjacent residues and (2) at least one nonclassicalcadherin CAR sequence or an analogue thereof. The intramolecular bondmay be a backbone to backbone, side-chain to backbone or side-chain toside-chain bond (i.e., terminal functional groups of a linear peptideand/or side chain functional groups of a terminal or interior residuemay be linked to achieve cyclization). Preferred intramolecular bondsinclude, but are not limited to, disulfide, amide and thioether bonds.One or more of any of the above nonclassical cadherin CAR sequences, oran analogue or mimetic thereof, may be incorporated into a cyclicpeptide, with or without one or more other adhesion molecule bindingsites. Additional adhesion molecule binding sites are described ingreater detail below.

[0109] The size of a cyclic peptide ring generally ranges from 5 toabout 15 residues, preferably from 5 to 10 residues. Additionalresidue(s) may be present on the N-terminal and/or C-terminal side of anonclassical cadherin CAR sequence, and may be derived from sequencesthat flank a nonclassical cadherin CAR sequence, with or without aminoacid substitutions and/or other modifications. Alternatively, additionalresidues present on one or both sides of the CAR sequence(s) may beunrelated to an endogenous sequence (e.g., residues that facilitatecyclization, purification or other manipulation and/or residues having atargeting or other function).

[0110] Within certain embodiments, a modulating agent may comprise acyclic peptide that contains a nonclassical cadherin CAR sequence asprovided in Table I (or a portion of such a CAR sequence). Certaincyclic peptides have the formula:

[0111] Within this formula, W is a tripeptide selected from the groupconsisting of EEY, DDK, EAQ, DAE, NEN, ESE, DSG, DEN, EPK, DAN, EEF,NDV, DET, DPK, DDT, DAN, DKF, DEL, DAD, NNK, DLV, NRD, DPS, NQK, NRN,NKD, EKD, ERD, DPV, DSV, DLY, DSN, DSS, DEK and NEK; X₁, and X₂ areoptional, and if present, are independently selected from the groupconsisting of amino acid residues and combinations thereof in which theresidues are linked by peptide bonds, and wherein X₁ and X₂independently range in size from 0 to 10 residues, such that the sum ofresidues contained within X₁ and X₂ ranges from 1 to 12; Y₁ and Y₂ areindependently selected from the group consisting of amino acid residues,and wherein a covalent bond is formed between residues Y₁ and Y₂; and Z₁and Z₂ are optional, and if present, are independently selected from thegroup consisting of amino acid residues and combinations thereof inwhich the residues are linked by peptide bonds.

[0112] Cyclic peptides may comprise any of the above CAR sequence(s).Such cyclic peptides may be used as modulating agents withoutmodification, or may be incorporated into a modulating agent.

[0113] For example, cyclic peptides may comprise any of the aboveOB-cadherin CAR sequence(s). Representative cyclic peptides includeCDDKC (SEQ ID NO₆₆₉), CIDDKC (SEQ ID NO:670), CDDKSC (SEQ ID NO:671),CVIDDKC (SEQ ID NO:672), CIDDKSC (SEQ ID NO:673), CVIDDKSC (SEQ IDNO:674), CDDKSGC (SEQ ID NO:675), CIDDKSGC (SEQ ID NO:676), CVIDDKSGC(SEQ ID NO:677), CFVIDDKC (SEQ ID NO:678), CFVIDDKSC (SEQ ID NO:679),CFVIDDKSGC (SEQ ID NO:680), CIFVIDDKC (SEQ ID NO:681), CIFVIDDKSC (SEQID NO:682), CIFVIDDKSGC (SEQ ID NO:683), DDDKK (SEQ ID NO:684), DIDDKK(SEQ ID NO:685), DVIDDKK (SEQ ID NO:686), DFVIDDKK (SEQ ID NO:687),DIFVIDDKK (SEQ ID NO:688), EDDKK (SEQ ID NO:689), EIDDKK (SEQ IDNO:690), EVIDDKK (SEQ ID NO:691), EFVIDDKK (SEQ ID NO:692), EIFVIDDKK(SEQ ID NO:693), FVIDDK (SEQ ID NO:694), FVIDDKS (SEQ ID NO:695),FVIDDKSG (SEQ ID NO:696), KDDKD (SEQ ID NO:697), KIDDKD (SEQ ID NO:698),KDDKSD (SEQ ID NO:699), KVIDDKD (SEQ ID NO:700), KIDDKSD (SEQ IDNO:701), KVIDDKSD (SEQ ID NO:702), KDDKSGD (SEQ ID NO:703), KIDDKSGD(SEQ ID NO:704), KVIDDKSGD (SEQ ID NO:705), KFVIDDKD (SEQ ID NO:706),KFVIDDKSD (SEQ ID NO:707), KFVIDDKSGD (SEQ ID NO:708), KIFVIDDKD (SEQ IDNO:709), KIFVIDDKSD (SEQ ID NO:710), KIFVIDDKSGD (SEQ ID NO:711), VIDDK(SEQ ID NO:712), IDDKS (SEQ ID NO:713), VIDDKS (SEQ ID NO:714), VIDDKSG(SEQ ID NO:715), DDKSG (SEQ ID NO:716), IDDKSG (SEQ ID NO:717), IFVIDDK(SEQ ID NO:718), IFVIDDKS (SEQ ID NO:719), IFVIDDKSG (SEQ ID NO:720),KDDKE (SEQ ID NO:721), KIDDKE (SEQ ID NO:722), KDDKSE (SEQ ID NO:723),KVIDDKE (SEQ ID NO:724), KIDDKSE (SEQ ID NO:725), KVIDDKSE (SEQ IDNO:726), KDDKSGE (SEQ ID NO:727), KIDDKSGE (SEQ ID NO:728), KVIDDKSGE(SEQ ID NO:729), KFVIDDKE (SEQ ID NO:730), KFVIDDKSE (SEQ ID NO:731),KFVIDDKSGE (SEQ ID NO:732), KIFVIDDKE (SEQ ID NO:733), KIFVIDDKSE (SEQID NO:734), KIFVIDDKSGE (SEQ ID NO:735), CEEYC (SEQ ID NO:736), CIEEYC(SEQ ID NO:737), CEEYTC (SEQ ID NO:738), CVIEEYC (SEQ ID NO:739),CIEEYTC (SEQ ID NO:740), CVIEEYTC (SEQ ID NO:741), CEEYTGC (SEQ IDNO:742), CIEEYTGC (SEQ ID NO:743), CVIEEYTGC (SEQ ID NO:744), CFVIEEYC(SEQ ID NO:745), CFVIEEYTC (SEQ ID NO:746), CFVIEEYTGC (SEQ ID NO:747),CFFVIEEYC (SEQ ID NO:748), CFFVIEEYTC (SEQ ID NO:749), CFFVIEEYTGC (SEQID NO:750), KEEYD (SEQ ID NO:751), KIEEYD (SEQ ID NO:752), KEEYTD (SEQID NO:753), KVIEEYD (SEQ ID NO:754), KIEEYTD (SEQ ID NO:755), KVIEEYTD(SEQ ID NO:756), KEEYTGCD (SEQ ID NO:757), KIEEYTGD (SEQ ID NO:758),KVIEEYTGD (SEQ ID NO:759), KFVIEEYD (SEQ ID NO:760), KFVIEEYTD (SEQ IDNO:761), KFVIEEYTGD (SEQ ID NO:762), KFFVIEEYD (SEQ ID NO:763),KFFVIEEYTD (SEQ ID NO:764), KFFVIEEYTGD (SEQ ID NO:765), EEEYK (SEQ IDNO:766), EIEEYK (SEQ ID NO:767), EEEYTK (SEQ ID NO:768), EVIEEYK (SEQ IDNO:769), EIEEYTK (SEQ ID NO:770), EVIEEYTK (SEQ ID NO:771), EEEYTGK (SEQID NO:772), EIEEYTGK (SEQ ID NO:773), EVIEEYTGK (SEQ ID NO:774),EFVIEEYK (SEQ ID NO:775), EFVIEEYTK (SEQ ID NO:776), EFVIEEYTGK (SEQ IDNO:777), EFFVIEEYK (SEQ ID NO:778), EFFVIEEYTK (SEQ ID NO:779),EFFVIEEYTGK (SEQ ID NO:780), DCEEYK (SEQ ID NO:781), DIEEYCK (SEQ IDNO:782), DEEYTK (SEQ ID NO:783), DVIEEYK (SEQ ID NO:784), DIEEYTK (SEQID NO:785), DVIEEYTK (SEQ ID NO:786), DEEYTGK (SEQ ID NO:787), DIEEYTGK(SEQ ID NO:788), DVIEEYTGK (SEQ ID NO:789), DFVIEEYK (SEQ ID NO:790),DFVIEEYTK (SEQ ID NO:791), DFVIEEYTGK (SEQ ID NO:792), DFFVIEEYK (SEQ IDNO:793), DFFVIEEYTK (SEQ ID NO:794), DFFVIEEYTGK (SEQ ID NO:795), KEEYE(SEQ ID NO:796), KIEEYE (SEQ ID NO:797), KEEYTE (SEQ ID NO:798), KVIEEYE(SEQ ID NO:799), KIEEYTE (SEQ ID NO:800), KVIEEYTE (SEQ ID NO:801),KEEYTGE (SEQ ID NO:802), KIEEYTGE (SEQ ID NO:803), KVIEEYTGE (SEQ IDNO:804), KFVIEEYE (SEQ ID NO:805), KFVIEEYTE (SEQ ID NO:806), KFVIEEYTGE(SEQ ID NO:807), KFFVIEEYE (SEQ ID NO:808), KFFVIEEYTE (SEQ ID NO:809),KFFVIEEYTGE (SEQ ID NO:810), VIEEY (SEQ ID NO:811), IEEYT (SEQ IDNO:812), VIEEYT (SEQ ID NO:813), EEYTG (SEQ ID NO:814), IEEYTG (SEQ IDNO:815), VIEEYTG (SEQ ID NO:816), FVIEEY (SEQ ID NO:817), FVIEEYT (SEQID NO:818), FVIEEYTG (SEQ ID NO:819), FFVIEEY (SEQ ID NO:820), FFVIEEYT(SEQ ID NO:821), FFVIEEYTG (SEQ ID NO:822), CEAQC (SEQ ID NO:823),CVEAQC (SEQ ID NO:824), CEAQTC (SEQ ID NO:825), CSVEAQC (SEQ ID NO:826),CVEAQTC (SEQ ID NO:827), CSVEAQTC (SEQ ID NO:828), CEAQTGC (SEQ IDNO:829), CVEAQTGC (SEQ ID NO:830), CSVEAQTGC (SEQ ID NO:831), CFSVEAQC(SEQ ID NO:832), CFSVEAQTC (SEQ ID NO:833), CFSVEAQTGC (SEQ ID NO:834),CYFSVEAQC (SEQ ID NO:835), CYFSVEAQTC (SEQ ID NO:836), CYFSVEAQTGC (SEQID NO:837), KEAQD (SEQ ID NO:838), KVEAQD (SEQ ID NO:839), KEAQTD (SEQID NO:840), KSVEAQD (SEQ ID NO:841), KVEAQTD (SEQ ID NO:842), KSVEAQTD(SEQ ID NO:843), KEAQTGD (SEQ ID NO:844), KVEAQTGD (SEQ ID NO:845),KSVEAQTGD (SEQ ID NO:846), KFSVEAQD (SEQ ID NO:847), KFSVEAQTD (SEQ IDNO:848), KFSVEAQTGD (SEQ ID NO:849), KYFSVEAQD (SEQ ID NO:850),KYFSVEAQTD (SEQ ID NO:851), KYFSVEAQTGD (SEQ ID NO:852), EEAQK (SEQ IDNO:853), EVEAQK (SEQ ID NO:854), EEAQTK (SEQ ID NO:855), ESVEAQK (SEQ IDNO:856), EVEAQTK (SEQ ID NO:857), ESVEAQTK (SEQ ID NO:858), EEAQTGK (SEQID NO:859), EVEAQTGK (SEQ ID NO:860), ESVEAQTGK (SEQ ID NO:861),EFSVEAQK (SEQ ID NO:862), EFSVEAQTK (SEQ ID NO:863), EFSVEAQTGK (SEQ IDNO:864), EYFSVEAQK (SEQ ID NO:865), EYFSVEAQTK (SEQ ID NO:866),EYFSVEAQTGK (SEQ ID NO:867), DEAQK (SEQ ID NO:868), DVEAQK (SEQ IDNO:869), DEAQTK (SEQ ID NO:870), DSVEAQK (SEQ ID NO:871), DVEAQTK (SEQID NO:872), DSVEAQTK (SEQ ID NO:873), DEAQTGK (SEQ ID NO:874), DVEAQTGK(SEQ ID NO:875), DSVEAQTGK (SEQ ID NO:876), DFSVEAQK (SEQ ID NO:877),DFSVEAQTK (SEQ ID NO:878), DFSVEAQTGK (SEQ ID NO:879), DYFSVEAQK (SEQ IDNO:880), DYFSVEAQTK (SEQ ID NO:881), DYFSVEAQTGK (SEQ ID NO:882), KEAQE(SEQ ID NO:883), KVEAQE (SEQ ID NO:884), KEAQTE (SEQ ID NO:885), KSVEAQE(SEQ ID NO:886), KVEAQTE (SEQ ID NO:887), KSVEAQTE (SEQ ID NO:888),KEAQTGE (SEQ ID NO:889), KVEAQTGE (SEQ ID NO:890), KSVEAQTGE (SEQ IDNO:891), KFSVEAQE (SEQ ID NO:892), KFSVEAQTE (SEQ ID NO:893), KFSVEAQTGE(SEQ ID NO:894), KYFSVEAQE (SEQ ID NO:895), KYFSVEAQTE (SEQ ID NO:896),KYFSVEAQTGE (SEQ ID NO:897), SVEAQ (SEQ ID NO:898), VEAQT (SEQ IDNO:899), SVEAQT (SEQ ID NO:900), EAQTG (SEQ ID NO:901), VEAQTG (SEQ IDNO:902), SVEAQTG (SEQ ID NO:903), FSVEAQ (SEQ ID NO:904), FSVEAQT (SEQID NO:905), FSVEAQTG (SEQ ID NO:906), YFSVEAQ (SEQ ID NO:907), YFSVEAQT(SEQ ID NO:908) and YFSVEAQTG (SEQ ID NO:909). Within the context of thepresent invention, underlined sequences are cyclized using any suitablemethod, as described herein.

[0114] Similarly, cyclic peptides may comprise any of the abovecadherin-5 CAR sequence(s). Representative cyclic peptides include:CDAEC (SEQ ID NO:910), CVDAEC (SEQ ID NO:911), CDAETC (SEQ ID NO:912),CRVDAEC (SEQ ID NO:913), CVDAETC (SEQ ID NO:914), CRVDAETC (SEQ IDNO:915), CDAETGC (SEQ ID NO:916), CCDAETGC (SEQ ID NO:917), CRVDAETGC(SEQ ID NO:918), CFRVDAEC (SEQ ID NO:919), CFRVDAETC (SEQ ID NO:920),CFRVDAETGC (SEQ ID NO:921), CVFRVDAEC (SEQ ID NO:922), CVFRVDAETC (SEQID NO:923), CVFRVDAETGC (SEQ ID NO:924), DDAEK (SEQ ID NO:925), DVDAEK(SEQ ID NO:926), DRVDAEK (SEQ ID NO:927), DFRVDAEK (SEQ ID NO:928),DVFRVDAEK (SEQ ID NO:929), EDAEK (SEQ ID NO:930), EVDAEK (SEQ IDNO:931), ERVDAEK (SEQ ID NO:932), EFRVDAEK (SEQ ID NO:933), EVFRVDAEK(SEQ ID NO:934), KDAED (SEQ ID NO:935), KVDAED (SEQ ID NO:936), KDAETD(SEQ ID NO:937), KRVDAED (SEQ ID NO:938), KVDAETD (SEQ ID NO:939),KRVDAETD (SEQ ID NO:940), KDAETGD (SEQ ID NO:941), KVDAETGD (SEQ IDNO:942), KRVDAETGD (SEQ ID NO:943), KFRVDAED (SEQ ID NO:944), KFRVDAETD(SEQ ID NO:945), KFRVDAETGD (SEQ ID NO:946), KVFRVDAED (SEQ ID NO:947),KVFRVDAETD (SEQ ID NO:948), KVFRVDAETGD (SEQ ID NO:949), VDAEK (SEQ IDNO:950), IDAES (SEQ ID NO:951), VDAES (SEQ ID NO:952), DAETG (SEQ IDNO:953), VDAETG (SEQ ID NO:954), KDAEE (SEQ ID NO:955), KVDAE (SEQ IDNO:956), KDAETE (SEQ ID NO:957), KRVDAE (SEQ ID NO:958), KVDAETE (SEQ IDNO:959), KRVDAETE (SEQ ID NO:960), KDAETGE (SEQ ID NO:961), KVDAETGE(SEQ ID NO:962), KRVDAETGE (SEQ ID NO:962), KFRVDAE (SEQ ID NO:964),KFRVDAETE (SEQ ID NO:965), KFRVDAETGE (SEQ ID NO:966), KVFRVDAE (SEQ IDNO:967), KVFRVDAETE (SEQ ID NO:968), KVFRVDAETGE (SEQ ID NO:969), VDAET(SEQ ID NO:970), VDAETG (SEQ ID NO:971), DAETG (SEQ ID NO:972), RVDAE(SEQ ID NO:973), RVDAET (SEQ ID NO:974), RVDAETG (SEQ ID NO:975), FRVDAE(SEQ ID NO:976), FRVDAET (SEQ ID NO:977), FRVDAETG (SEQ ID NO:978),VFRVDAE (SEQ ID NO:979), VFRVDAET (SEQ ID NO:980) and VFRVDAETG (SEQ IDNO:981).

[0115] Any cadherin-6 CAR sequence(s) may be formulated into a cyclicpeptide. Representative cyclic peptides include: CNENC (SEQ ID NO:983),CINENC (SEQ ID NO:984), CNENTC (SEQ ID NO:985), CIINENC (SEQ ID NO:986),CINENTC (SEQ ID NO:987), CIINENTC (SEQ ID NO:988), CNENTGC (SEQ IDNO:989), CINENTGC (SEQ ID NO:990), CIINENTGC (SEQ ID NO:991), CFIINENC(SEQ ID NO:992), CFIINENTC (SEQ ID NO:993), CFIINENTGC (SEQ ID NO:994),CLFIINENC (SEQ ID NO:995), CLFIINENTC (SEQ ID NO:996), CLFIINENTGC (SEQID NO:997), DNENK (SEQ ID NO:998), DINENK (SEQ ID NO:999), DIINENK (SEQID NO:1000), DFIINENK (SEQ ID NO:1001), DLFIINENK (SEQ ID NO:1002),DNENTK (SEQ ID NO:982), DINENTK (SEQ ID NO:2883), DIINENTK (SEQ IDNO:2884), DFIINENTK (SEQ ID NO:2885), DLFIINENTK (SEQ ID NO:2946),DNENTGK (SEQ ID NO:2947), DINENTGK (SEQ ID NO:2948), DIINENTGK (SEQ IDNO:3009), DFIINENTGK (SEQ ID NO:3010), DLFIINENTGK (SEQ ID NO:3011),ENENTK (SEQ ID NO:3055), EINENTK (SEQ ID NO:3630), EIINENTK (SEQ IDNO:3736), EFIINENTK (SEQ ID NO:3842), ELFIINENTK (SEQ ID NO:3890),ENENTGK (SEQ ID NO:3891), EINENTGK (SEQ ID NO:3892), EIINENTGK (SEQ IDNO:3893), EFIINENTGK (SEQ ID NO:3894), ELFIINENTGK (SEQ ID NO:3895),ENENK (SEQ ID NO:1003), EINENK (SEQ ID NO:1004), EIINENK (SEQ IDNO:1005), EFIINENK (SEQ ID NO:1006), ELFIINENK (SEQ ID NO:1007), KNEND(SEQ ID NO:1008), KINEND (SEQ ID NO:1009), KNENTD (SEQ ID NO:1010),KIINEND (SEQ ID NO:1011), KINENTD (SEQ ID NO:1012), KIINENTD (SEQ IDNO:1013), KNENTGD (SEQ ID NO:1014), KINENTGD (SEQ ID NO:1015), KIINENTGD(SEQ ID NO:1016), KFIINEND (SEQ ID NO:1017), KFIINENTD (SEQ ID NO:1018),KFIINENTGD (SEQ ID NO:1019), KLFIINEND (SEQ ID NO:1020), KLFIINENTD (SEQID NO:1021), KLFIINENTGD (SEQ ID NO:1022), VNENT (SEQ ID NO:1023), INENT(SEQ ID NO:1024), IINENT (SEQ ID NO:1025), NENTG (SEQ ID NO:1026),INENTG (SEQ ID NO:1027) KNENE (SEQ ID NO:1028), KINENE (SEQ ID NO:1029),KNENTE (SEQ ID NO:1030), KIINENE (SEQ ID NO:1031), KINENTE (SEQ IDNO:1032), KIINENTE (SEQ ID NO:1033), KNENTGE (SEQ ID NO:1034), KINENTGE(SEQ ID NO:1035), KIINENTGE (SEQ ID NO:1036), KFIINENE (SEQ ID NO:1037),KFIINENTE (SEQ ID NO:1038), KFIINENTGE (SEQ ID NO:1039), KLFIINENE (SEQID NO:1040), KLFIINENTE (SEQ ID NO:1041), KLFIINENTGE (SEQ ID NO:1042),IINEN (SEQ ID NO:1043), FIINEN (SEQ ID NO:1044), FIINENT (SEQ IDNO:1045), FIINENTG (SEQ ID NO:1046), LFIINEN (SEQ ID NO:1047), LFIINENT(SEQ ID NO:1048), LFIINENTG (SEQ ID NO:1049), CEEYC (SEQ ID NO:1050),CEEYTC (SEQ ID NO:1051), CEEYTGC (SEQ ID NO:1052), CLEEYC (SEQ IDNO:1053), CLEEYTC (SEQ ID NO:1054), CLEEYTGC (SEQ ID NO:1055), CLLEEYC(SEQ ID NO:1056), CLLEEYTGC (SEQ ID NO:1057), CFLLEEYC (SEQ ID NO:1058),CLLEEYTC (SEQ ID NO:1059), CFLLEEYTGC (SEQ ID NO:1060), CFFLLEEYC (SEQID NO:1061), CFFLLEEYTC (SEQ ID NO:1062), CFFLLEEYTGC (SEQ ID NO:1063),CESEC (SEQ ID NO:1064), CESETC (SEQ ID NO:1065), CESETGC (SEQ IDNO:1066), CVESEC (SEQ ID NO:1067), CVSESTC (SEQ ID NO:1068), CVESETGC(SEQ ID NO:1069), CSVESEC (SEQ ID NO:1070), CSVESETC (SEQ ID NO:1071),CSVESETGC (SEQ ID NO:1072), CFSVESEC (SEQ ID NO:1073), CFSVESETC (SEQ IDNO:1074), CFSVESETGC (SEQ ID NO:1075), CYFSVESEC (SEQ ID NO:1076),CYFSVESETC (SEQ ID NO:1077), CYFSVESETGC (SEQ ID NO:1078), CDSGC (SEQ IDNO:1079), CDSGNC (SEQ ID NO:1080), CDSGNGC (SEQ ID NO:1081), CIDSGC (SEQID NO:1082), CIDSGNC (SEQ ID NO:1083), CIDSGNGC (SEQ ID NO:1084),CNIDSGC (SEQ ID NO:1085), CNIDSGNC (SEQ ID NO:1086), CNIDSGNGC (SEQ IDNO:1087), CFNIDSGC (SEQ ID NO:1088), CFNIDSGNC (SEQ ID NO:1089),CFNIDSGNGC (SEQ ID NO:1090), CIFNIDSGC (SEQ ID NO:1091), CIFNIDSGNC (SEQID NO:1092), CIFNIDSGNGC (SEQ ID NO:1093), KEEYD (SEQ ID NO:1094),KLEEYD (SEQ ID NO:1095), KEEYTD (SEQ ID NO:1096), KEEYTGD (SEQ IDNO:1097), KLEEYTD (SEQ ID NO:1098), KLEEYTGD (SEQ ID NO:1099), KLLEEYD(SEQ ID NO:1100), KLLEEYTGD (SEQ ID NO:1101), KFLLEEYD (SEQ ID NO:1102),KLLEEYTD (SEQ ID NO:1103), KFLLEEYTGD (SEQ ID NO:1104), KFFLLEEYD (SEQID NO:1105), KFFLLEEYTD (SEQ ID NO:1106), KFFLLEEYTGD (SEQ ID NO:1107),KESED (SEQ ID NO:1108), KESETD (SEQ ID NO:1109), KESETGD (SEQ IDNO:1110), KVESED (SEQ ID NO:1111), KVSESTD (SEQ ID NO:1112), KVESETGD(SEQ ID NO: 1113), KSVESED (SEQ ID NO: 1114), KSVESETD (SEQ ID NO:1115), KSVESETGD (SEQ ID NO:1116), KFSVESED (SEQ ID NO:1117), KFSVESETD(SEQ ID NO:1118), KFSVESETGD (SEQ ID NO:1119), KYFSVESED (SEQ IDNO:1120), KYFSVESETD (SEQ ID NO:1121), KYFSVESETGD (SEQ ID NO:1122),KDSGD (SEQ ID NO: 1123), KDSGND (SEQ ID NO:1124), KDSGNGD (SEQ IDNO:1125), KIDSGD (SEQ ID NO:1126), KIDSGND (SEQ ID NO:1127), KIDSGNGD(SEQ ID NO:1128), KNIDSGD (SEQ ID NO:1129), KNIDSGND (SEQ ID NO:1130),KNIDSGNGD (SEQ ID NO:1131), KFNIDSGD (SEQ ID NO:1132), KFNIDSGND (SEQ IDNO:1133), KFNIDSGNGD (SEQ ID NO:1134), KIFNIDSGD (SEQ ID NO:1135),KIFNIDSGND (SEQ ID NO:1136), KIFNIDSGNGD (SEQ ID NO: 1137), EEEYK (SEQID NO: 1138), EEEYTK (SEQ ID NO: 1139), EEEYTGK (SEQ ID NO:1140), ELEEYK(SEQ ID NO:1141), EEEYTK (SEQ ID NO:1142), ELEEYTGK (SEQ ID NO:1143),ELLEEYK (SEQ ID NO:1144), ELLEEYTGK (SEQ ID NO:1145), EFLLEEYK (SEQ IDNO:1146), ELLEEYTK (SEQ ID NO:1147), EFLLEEYTGK (SEQ ID NO:1148),EFFLLEEYK (SEQ ID NO:1149), EFFLLEEYTK (SEQ ID NO: 1150), EFFLLEEYTGK(SEQ ID NO: 1151), EESEK (SEQ ID NO:1152), EESETK (SEQ ID NO:1153),EESETGK (SEQ ID NO:1154), EVESEK (SEQ ID NO:1155), EVSESTK (SEQ IDNO:1156), EVESETGK (SEQ ID NO:1157), ESVESEK (SEQ ID NO:1158), ESVESETK(SEQ ID NO:1159), ESVESETGK (SEQ ID NO:1160), EFSVESEK (SEQ ID NO:1161),EFSVESETK (SEQ ID NO:1162), EFSVESETGK (SEQ ID NO:1163), EYFSVESEK (SEQID NO:1164), EYFSVESETK (SEQ ID NO:1165), EYFSVESETGK (SEQ ID NO:1166),EDSGK (SEQ ID NO:1167), EDSGNK (SEQ ID NO:1168), EDSGNGK (SEQ IDNO:1169), EIDSGK (SEQ ID NO:1170), EIDSGNK (SEQ ID NO:1171), EIDSGNGK(SEQ ID NO:1172), ENIDSGK (SEQ ID NO:1173), ENIDSGNK (SEQ ID NO:1174),ENIDSGNGK (SEQ ID NO:1175), EFNIDSGK (SEQ ID NO:1176), EFNIDSGNK (SEQ IDNO:1177), EFNIDSGNGK (SEQ ID NO:1178), EIFNIDSGK (SEQ ID NO:1179),EIFNIDSGNK (SEQ ID NO:1180), EIFNIDSGNGK (SEQ ID NO:1181), DEEYK (SEQ IDNO:1182), DLEEYK (SEQ ID NO:1183), DLEEYTK (SEQ ID NO:1184), DLEEYTGK(SEQ ID NO:1185), DLLEEYK (SEQ ID NO:1186), DLLEEYTGK (SEQ ID NO: 1187),DFLLEEYK (SEQ ID NO:1188), DLLEEYTK (SEQ ID NO:1189), DFLLEEYTGK (SEQ IDNO:1190), DFFLLEEYK (SEQ ID NO:1191), DFFLLEEYTK (SEQ ID NO:1192),DFFLLEEYTGK (SEQ ID NO: 1193), DESEK (SEQ ID NO:1194), DESETK (SEQ IDNO: 1195), DESETGK (SEQ ID NO: 1196), DVESEK (SEQ ID NO: 1197), DVSESTK(SEQ ID NO: 1198), DVESETGK (SEQ ID NO:1199), DSVESEK (SEQ ID NO:1200),DSVESETK (SEQ ID NO:1201), DSVESETGK (SEQ ID NO:1202), DFSVESEK (SEQ IDNO:1203), DFSVESETK (SEQ ID NO:1204), DFSVESETGK (SEQ ID NO:1205),DYFSVESEK (SEQ ID NO:1206), DYFSVESETK (SEQ ID NO:1207), DYFSVESETGK(SEQ ID NO:1208), DDSGK (SEQ ID NO:1209), DDSGNK (SEQ ID NO:1210),DDSGNGK (SEQ ID NO:1211), DIDSGK (SEQ ID NO:1212), DIDSGNK (SEQ IDNO:1213), DIDSGNGK (SEQ ID NO:1214), DNIDSGK (SEQ ID NO:1215), DNIDSGNK(SEQ ID NO:1216), DNIDSGNGK (SEQ ID NO:1217), DFNIDSGK (SEQ ID NO:1218),DFNIDSGNK (SEQ ID NO:1219), DFNIDSGNGK (SEQ ID NO:1220), DIFNIDSGK (SEQID NO:1221), DIFNIDSGNK (SEQ ID NO:1222), DIFNIDSGNGK (SEQ ID NO:1223),KEEYE (SEQ ID NO:1224), KLEEYE (SEQ ID NO:1225), KLEEYTE (SEQ IDNO:1226), KLEEYTGE (SEQ ID NO:1227), KLLEEYE (SEQ ID NO:1228), KLLEEYTGE(SEQ ID NO:1229), KFLLEEYE (SEQ ID NO:1230), KLLEEYTE (SEQ ID NO:1231),KFLLEEYTGE (SEQ ID NO:1232), KFFLLEEYE (SEQ ID NO:1233), KFFLLEEYTE (SEQID NO:1234), KFFLLEEYTGE (SEQ ID NO:1235), KNENE (SEQ ID NO:1236),KNENTE (SEQ ID NO:1237), KINENTGE (SEQ ID NO:1238), KESEE (SEQ IDNO:1239), KESETE (SEQ ID NO:1240), KESETGE (SEQ ID NO:1241), KVESEE (SEQID NO:1242) KVSESTE (SEQ ID NO:1243), KVESETGE (SEQ ID NO:1244), KSVESEE(SEQ ID NO:1245), KSVESETE (SEQ ID NO:1246), KSVESETGE (SEQ ID NO:1247),KFSVESEE (SEQ ID NO:1248), KFSVESETE (SEQ ID NO:1249), KFSVESETGE (SEQID NO:1250), KYFSVESEE (SEQ ID NO:1251), KYFSVESETE (SEQ ID NO:1252),KYFSVESETGE (SEQ ID NO:1253), KDSGE (SEQ ID NO:1254), KDSGNE (SEQ IDNO:1255), KDSGNGE (SEQ ID NO:1256), KIDSGE (SEQ ID NO:1257), KIDSGNE(SEQ ID NO:1258), KIDSGNGE (SEQ ID NO:1259), KNIDSGE (SEQ ID NO:1260),KNIDSGNE (SEQ ID NO:1261), KNIDSGNGE (SEQ ID NO:1262), KFNIDSGE (SEQ IDNO:1263), KFNIDSGNE (SEQ ID NO:1264), KFNIDSGNGE (SEQ ID NO:1265),KIFNIDSGE (SEQ ID NO:1266), KIFNIDSGNE (SEQ ID NO:1267), KIFNIDSGNGE(SEQ ID NO:1268), LEEYT (SEQ ID NO:1269), LEEYTG (SEQ ID NO:1270), LLEEY(SEQ ID NO:1271), LLEEYTG (SEQ ID NO:1272), FLLEEY (SEQ ID NO:1273),LLEEYT (SEQ ID NO:1274), FLLEEYTG (SEQ ID NO:1275), FFLLEEY (SEQ IDNO:1276), FFLLEEYT (SEQ ID NO:1277), FFLLEEYTG (SEQ ID NO:1278), ESETG(SEQ ID NO:1279), VSEST (SEQ ID NO:1280), VESETG (SEQ ID NO:1281), SVESE(SEQ ID NO:1282), SVESET (SEQ ID NO:1283), SVESETG (SEQ ID NO:1284),FSVESE (SEQ ID NO:1285), FSVESET (SEQ ID NO:1286), FSVESETG (SEQ IDNO:1287), YFSVESE (SEQ ID NO:1288), YFSVESET (SEQ ID NO:1289), YFSVESETG(SEQ ID NO:1290), DSGNG (SEQ ID NO:1291), IDSGN (SEQ ID NO:1292), IDSGNG(SEQ ID NO:1293), NIDSG (SEQ ID NO:1294), NIDSGN (SEQ ID NO:1295),NIDSGNG (SEQ ID NO:1296), FNIDSG (SEQ ID NO:1297), FNIDSGN (SEQ IDNO:1298), FNIDSGNG (SEQ ID NO:1299), IFNIDSG (SEQ ID NO:1300), IFNIDSGN(SEQ ID NO:1301) and IFNIDSGNG (SEQ ID NO:1302).

[0116] Representative cyclic peptides comprising a cadherin-7 CARsequence include: CDENC (SEQ ID NO:1303), CIDENC (SEQ ID NO:1304),CDENTC (SEQ ID NO:1305), CIIDENC (SEQ ID NO:1306), CIDENTC (SEQ IDNO:1307), CIIDENTC (SEQ ID NO:1308), CDENTGC (SEQ ID NO:1309), CIDENTGC(SEQ ID NO:1310), CIIDENTGC (SEQ ID NO:1311), CFIIDENC (SEQ ID NO:1312),CFIIDENTC (SEQ ID NO:1313), CFIIDENTGC (SEQ ID NO:1314), CIFIIDENC (SEQID NO:1315), CIFIIDENTC (SEQ ID NO:1316), CIFIIDENTGC (SEQ ID NO:1317),DDENK (SEQ ID NO:1319), DIDENK (SEQ ID NO:1320), DIIDENK (SEQ IDNO:1321), DFIIDENK (SEQ ID NO:1322), DIFIIDENK (SEQ ID NO:1323), DDENTK(SEQ ID NO:1318), DIDENTK (SEQ ID NO:1344), DIIDENTK (SEQ ID NO:3896),DFIIDENTK (SEQ ID NO:3897), DIFIIDENTK (SEQ ID NO:3898), DDENTGK (SEQ IDNO:3899), DIDENTGK (SEQ ID NO:3900), DIIDENTGK (SEQ ID NO:3901),DFIIDENTGK (SEQ ID NO:3902), DIFIIDENTGK (SEQ ID NO:3903), EDENTK (SEQID NO:3904), EIDENTK (SEQ ID NO:3905), EIIDENTK (SEQ ID NO:3906),EFIIDENTK (SEQ ID NO:3907), EIFIIDENTK (SEQ ID NO:3908), EDENTGK (SEQ IDNO:3909), EIDENTGK (SEQ ID NO:3910), EIIDENTGK (SEQ ID NO:3911),EFIIDENTGK (SEQ ID NO:3912), EIFIIDENTGK (SEQ ID NO:3913), EDENK (SEQ IDNO:1324), EIDENK (SEQ ID NO:1325), EIIDENK (SEQ ID NO:1326), EFIIDENK(SEQ ID NO:1327), EIFIIDENK (SEQ ID NO:1328), KDEND (SEQ ID NO:1329),KIDEND (SEQ ID NO:1330), KDENTD (SEQ ID NO:1331), KIIDEND (SEQ IDNO:1332), KIDENTD (SEQ ID NO:1333), KIIDENTD (SEQ ID NO:1334), KDENTGD(SEQ ID NO:1335), KIDENTGD (SEQ ID NO:1336), KIIDENTGD (SEQ ID NO:1337),KFIIDEND (SEQ ID NO:1338), KFIIDENTD (SEQ ID NO:1339), KFIIDENTGD (SEQID NO:1340), KIFIIDEND (SEQ ID NO:1341), KIFIIDENTD (SEQ ID NO:1342),KIFIIDENTGD (SEQ ID NO:1343), IDENT (SEQ ID NO:1345), IIDENT (SEQ IDNO:1346), DENTG (SEQ ID NO:1347), IDENTG (SEQ ID NO:1348) KDENE (SEQ IDNO:1349), KIDENE (SEQ ID NO:1350), KDENTE (SEQ ID NO:1351), KIIDENE (SEQID NO:1352), KIDENTE (SEQ ID NO:1353), KIIDENTE (SEQ ID NO:1354),KDENTGE (SEQ ID NO:1355), KIDENTGE (SEQ ID NO:1356), KIIDENTGE (SEQ IDNO:1357), KFIIDENE (SEQ ID NO:1358), KFIIDENTE (SEQ ID NO:1359),KFIIDENTGE (SEQ ID NO:1360), KIFIIDENE (SEQ ID NO:1361), KIFIIDENTE (SEQID NO:1362), KIFIIDENTGE (SEQ ID NO:1363), DDENTK (SEQ ID NO:1364),IIDEN (SEQ ID NO:1365), IIDENTG (SEQ ID NO:1366), FIIDEN (SEQ IDNO:1367), FIIDENT (SEQ ID NO:1368), FIIDENTG (SEQ ID NO:1369), IFIIDEN(SEQ ID NO:1370), IFIIDENT (SEQ ID NO:1371), IFIIDENTG (SEQ ID NO:1372),CEPKC (SEQ ID NO:1373), CEPKTC (SEQ ID NO:1374), CEPKTGC (SEQ IDNO:1375), CVEPKC (SEQ ID NO:1376), CVEPKTC (SEQ ID NO:1377), CVEPKTGC(SEQ ID NO:1378), CSVEPKC (SEQ ID NO:1379), CSVEPKTC (SEQ ID NO:1380),CSVEPKTGC (SEQ ID NO:1381), CFSVEPKC (SEQ ID NO:1382), CFSVEPKTC (SEQ IDNO:1383), CFSVEPKTGC (SEQ ID NO:1384), CYFSVEPKC (SEQ ID NO:1385),CYFSVEPKTC (SEQ ID NO:1386), CYFSVEPKTGC (SEQ ID NO:1387), CDANC (SEQ IDNO:1388), CDANSC (SEQ ID NO:1389), CDANSGC (SEQ ID NO:1390), CIDANC (SEQID NO:1391), CIDANSC (SEQ ID NO:1392), CIDANSGC (SEQ ID NO:1393),CNIDANC (SEQ ID NO:1394), CNIDANSC (SEQ ID NO:1395), CNIDANSGC (SEQ IDNO:1396), CFNIDANC (SEQ ID NO:1397), CFNIDANSC (SEQ ID NO:1398),CFNIDANSGC (SEQ ID NO:1399), CYFNIDANC (SEQ ID NO:1400), CYFNIDANSC (SEQID NO:1401), CYFNIDANSGC (SEQ ID NO:1402), EEPKK (SEQ ID NO:1403),EEPKTK (SEQ ID NO:1404), EEPKTGK (SEQ ID NO:1405), EVEPKK (SEQ IDNO:1406), EVEPKTK (SEQ ID NO:1407), EVEPKTGK (SEQ ID NO:1408), ESVEPKK(SEQ ID NO:1409), ESVEPKTK (SEQ ID NO:1410), ESVEPKTGK (SEQ ID NO:1411),EFSVEPKK (SEQ ID NO:1412), EFSVEPKTK (SEQ ID NO:1413), EFSVEPKTGK (SEQID NO:1414), EYFSVEPKK (SEQ ID NO:1415), EYFSVEPKTK (SEQ ID NO:1416),EYFSVEPKTGK (SEQ ID NO:1417), EDANK (SEQ ID NO:1418), EDANSK (SEQ IDNO:1419), EDANSGK (SEQ ID NO:1420), EIDANK (SEQ ID NO:1421), EIDANSK(SEQ ID NO:1422), EIDANSGK (SEQ ID NO:1423), ENIDANK (SEQ ID NO:1424),ENIDANSK (SEQ ID NO:1425), ENIDANSGK (SEQ ID NO:1426), EFNIDANK (SEQ IDNO:1427), EFNIDANSK (SEQ ID NO:1428), EFNIDANSGK (SEQ ID NO:1429),EYFNIDANK (SEQ ID NO:1430), EYFNIDANSK (SEQ ID NO:1431), EYFNIDANSGK(SEQ ID NO: 1432), KDAND (SEQ ID NO: 1433), KIDAND (SEQ ID NO:1434),KDANSD (SEQ ID NO:1435), KNIDAND (SEQ ID NO:1436), KIDANSD (SEQ IDNO:1437), KNIDANSD (SEQ ID NO:1438), KDANSGD (SEQ ID NO:1439), KIDANSGD(SEQ ID NO:1440), KNIDANSGD (SEQ ID NO:1441), KFNIDAND (SEQ ID NO:1442),KFNIDANSD (SEQ ID NO:1443), KFNIDANSGD (SEQ ID NO:1444), KYFNIDAND (SEQID NO:1445), KYFNIDANSD (SEQ ID NO:1446), KYFNIDANSGD (SEQ ID NO:1447),KEPKD (SEQ ID NO:1448), KEPKTD (SEQ ID NO:1449), KEPKTGD (SEQ IDNO:1450), KVEPKD (SEQ ID NO:1451), KVEPKTD (SEQ ID NO:1452), KVEPKTGD(SEQ ID NO:1453), KSVEPKD (SEQ ID NO:1454), KSVEPKTD (SEQ ID NO:1455),KSVEPKTGD (SEQ ID NO:1456), KFSVEPKD (SEQ ID NO:1457), KFSVEPKTD (SEQ IDNO:1458), KFSVEPKTGD (SEQ ID NO:1459), KYFSVEPKD (SEQ ID NO:1460),KYFSVEPKTD (SEQ ID NO:1461), KYFSVEPKTGD (SEQ ID NO:1462), KDAND (SEQ IDNO:1463), KDANSD (SEQ ID NO:1464), KDANSGD (SEQ ID NO:1465), KIDAND (SEQID NO:1466), KIDANSD (SEQ ID NO:1467), KIDANSGD (SEQ ID NO:1468),KNIDAND (SEQ ID NO:1469), KNIDANSD (SEQ ID NO:1470), KNIDANSGD (SEQ IDNO:1471), KFNIDAND (SEQ ID NO:1472), KFNIDANSD (SEQ ID NO:1473),KFNIDANSGD (SEQ ID NO:1474), KYFNIDAND (SEQ ID NO:1475), KYFNIDANSD (SEQID NO:1476), KYFNIDANSGD (SEQ ID NO:1477)₁ DEPKK (SEQ ID NO:1478),DEPKTK (SEQ ID NO:1479), DEPKTGK (SEQ ID NO:1480), DVEPKK (SEQ IDNO:1481), DVEPKTK (SEQ ID NO:1482), DVEPKTGK (SEQ ID NO:1483), DSVEPKK(SEQ ID NO:1484), DSVEPKTK (SEQ ID NO:1485), DSVEPKTGK (SEQ ID NO:1486),DFSVEPKK (SEQ ID NO:1487), DFSVEPKTK (SEQ ID NO:1488), DFSVEPKTGK (SEQID NO:1489), DYFSVEPKK (SEQ ID NO:1490), DYFSVEPKTK (SEQ ID NO:1491),DYFSVEPKTGK (SEQ ID NO:1492), DDANK (SEQ ID NO:1493), DDANSK (SEQ IDNO:1494), DDANSGK (SEQ ID NO:1495), DIDANK (SEQ ID NO:1496), DIDANSK(SEQ ID NO:1497), DIDANSGK (SEQ ID NO:1498), DNIDANK (SEQ ID NO:1499),DNIDANSK (SEQ ID NO:1500), DNIDANSGK (SEQ ID NO:1501), DFNIDANK (SEQ IDNO:1502), DFNIDANSK (SEQ ID NO:1503), DFNIDANSGK (SEQ ID NO:1504),DYFNIDANK (SEQ ID NO:1505), DYFNIDANSK (SEQ ID NO:1506), DYFNIDANSGK(SEQ ID NO:1507)₁ KDENE (SEQ ID NO:1508), KDENTE (SEQ ID NO:1509),KDENTGE (SEQ ID NO:1510), KIDENE (SEQ ID NO:1511), KIDENTE (SEQ IDNO:1512), KIDENTGE (SEQ ID NO:1513), KIIDENE (SEQ ID NO:1514), KIIDENTE(SEQ ID NO:1515), KIIDENTGE (SEQ ID NO:1516), KFIIDENE (SEQ ID NO:1517),KFIIDENTE (SEQ ID NO:1518), KFIIDENTGE (SEQ ID NO:1519), KIFIIDENE (SEQID NO:1520), KIFIIDENTE (SEQ ID NO:1521), KIFIIDENTGE (SEQ ID NO:1522),KEPKE (SEQ ID NO:1523), KEPKTE (SEQ ID NO:1524), KEPKTGE (SEQ IDNO:1525), KVEPKE (SEQ ID NO:1526), KVEPKTE (SEQ ID NO:1527), KVEPKTGE(SEQ ID NO:1528), KSVEPKE (SEQ ID NO:1529), KSVEPKTE (SEQ ID NO:1530),KSVEPKTGE (SEQ ID NO:1531), KFSVEPKE (SEQ ID NO:1532), KFSVEPKTE (SEQ IDNO:1533), KFSVEPKTGE (SEQ ID NO:1534), KYFSVEPKE (SEQ ID NO:1535),KYFSVEPKTE (SEQ ID NO:1536), KYFSVEPKTGE (SEQ ID NO:1537), KDANE (SEQ IDNO:1538), KDANSE (SEQ ID NO:1539), KDANSGE (SEQ ID NO:1540), KIDANE (SEQID NO:1541), KIDANSE (SEQ ID NO:1542), KIDANSGE (SEQ ID NO:1543),KNIDANE (SEQ ID NO:1544), KNIDANSE (SEQ ID NO:1545), KNIDANSGE (SEQ IDNO:1546), KFNIDANE (SEQ ID NO:1547), KFNIDANSE (SEQ ID NO:1548),KFNIDANSGE (SEQ ID NO:1549), KYFNIDANE (SEQ ID NO:1550), KYFNIDANSE (SEQID NO:1551), KYFNIDANSGE (SEQ ID NO:1552), DENTG (SEQ ID NO:1553), IDENT(SEQ ID NO:1554), IDENTG (SEQ ID NO:1555), IIDEN (SEQ ID NO:1556),IIDENT (SEQ ID NO:1557), IIDENTG (SEQ ID NO:1558), FIIDEN (SEQ IDNO:1559), FIIDENT (SEQ ID NO:1560), FIIDENTG (SEQ ID NO:1561), IFIIDEN(SEQ ID NO:1562), IFIIDENT (SEQ ID NO:1563), IFIIDENTG (SEQ ID NO:1564),EPKTG (SEQ ID NO:1565), VEPKT (SEQ ID NO:1566), VEPKTG (SEQ ID NO:1567),SVEPK (SEQ ID NO:1568), SVEPKT (SEQ ID NO:1569), SVEPKTG (SEQ IDNO:1570), FSVEPK (SEQ ID NO:1571), FSVEPKT (SEQ ID NO:1572), FSVEPKTG(SEQ ID NO:1573), YFSVEPK (SEQ ID NO:1574), YFSVEPKT (SEQ ID NO:1575),YFSVEPKTG (SEQ ID NO:1576), DANSG (SEQ ID NO:1577), IDANS (SEQ IDNO:1578), IDANSG (SEQ ID NO:1579), NIDAN (SEQ ID NO:1580), NIDANS (SEQID NO:1581), NIDANSG (SEQ ID NO:1582), FNIDAN (SEQ ID NO:1583), FNIDANS(SEQ ID NO:1584), FNIDANSG (SEQ ID NO:1585), YFNIDAN (SEQ ID NO:1586),YFNIDANS (SEQ ID NO:1587) and YFNIDANSG (SEQ ID NO:1588).

[0117] Representative cyclic peptides comprising a cadherin-8 CARsequence include: CNDVC (SEQ ID NO:1589), CINDVC (SEQ ID NO:1590),CNDVTC (SEQ ID NO:1591), CQINDVC (SEQ ID NO:1592), CINDVTC (SEQ IDNO:1593), CQINDVTC (SEQ ID NO:1594), CNDVTGC (SEQ ID NO:1595), CINDVTGC(SEQ ID NO:1596), CQINDVTGC (SEQ ID NO:1597), CFQINDVC (SEQ ID NO:1598),CFQINDVTC (SEQ ID NO:1599), CFQINDVTGC (SEQ ID NO:1600), CIFQINDVC (SEQID NO:1601), CIFQINDVTC (SEQ ID NO:1602), CIFQINDVTGC (SEQ ID NO:1603),DNDVK (SEQ ID NO:1604), DINDVK (SEQ ID NO:1605), DQINDVK (SEQ IDNO:1606), DFQINDVK (SEQ ID NO:1607), DIFQINDVK (SEQ ID NO:1608), DNDVTK(SEQ ID NO:3924), DINDVTK (SEQ ID NO:3925), DQINDVTK (SEQ ID NO:3926),DFQINDVTK (SEQ ID NO:3927), DIFQINDVTK (SEQ ID NO:3928), DNDVTGK (SEQ IDNO:3929), DINDVTGK (SEQ ID NO:3930), DQINDVTGK (SEQ ID NO:3931),DFQINDVTGK (SEQ ID NO:3932), DIFQINDVTGK (SEQ ID NO:3933), ENDVTK (SEQID NO:3914), EINDVTK (SEQ ID NO:3915), EQINDVTK (SEQ ID NO:3916),EFQINDVTK (SEQ ID NO:3917), EIFQINDVTK (SEQ ID NO:3918), ENDVTGK (SEQ IDNO:3919), EINDVTGK (SEQ ID NO:3920), EQINDVTGK (SEQ ID NO:3921),EFQINDVTGK (SEQ ID NO:3922), EIFQINDVTGK (SEQ ID NO:3923), ENDVK (SEQ IDNO:1609), EINDVK (SEQ ID NO:1610), EQINDVK (SEQ ID NO:1611), EFQINDVK(SEQ ID NO:1612), EIFQINDVK (SEQ ID NO:1613), KNDVD (SEQ ID NO:1614),KINDVD (SEQ ID NO:1615), KNDVTD (SEQ ID NO:1616), KQINDVD (SEQ IDNO:1617), KINDVTD (SEQ ID NO:1618), KQINDVTD (SEQ ID NO:1619), KNDVTGD(SEQ ID NO:1620), KINDVTGD (SEQ ID NO:1621), KQINDVTGD (SEQ ID NO:1622),KFQINDVD (SEQ ID NO:1623), KFQINDVTD (SEQ ID NO:1624), KFQINDVTGD (SEQID NO:1625), KIFQINDVD (SEQ ID NO:1626), KIFQINDVTD (SEQ ID NO:1627),KIFQINDVTGD (SEQ ID NO:1628), VNDVT (SEQ ID NO:1629), INDVT (SEQ IDNO:1630), QINDVT (SEQ ID NO:1631), NDVTG (SEQ ID NO:1632), INVTG (SEQ IDNO:1633) KNDVE (SEQ ID NO:1634), KINDVE (SEQ ID NO:1635), KNDVTE (SEQ IDNO:1636), KQINDVE (SEQ ID NO:1637), KINDVTE (SEQ ID NO:1638), KQINDVTE(SEQ ID NO:1639), KNDVTGE (SEQ ID NO:1640), KINDVTGE (SEQ ID NO:1641),KQINDVTGE (SEQ ID NO:1642), KFQINDVE (SEQ ID NO:1643), KFQINDVTE (SEQ IDNO:1644), KFQINDVTGE (SEQ ID NO:1645), KIFQINDVE (SEQ ID NO:1646),KIFQINDVTE (SEQ ID NO:1647), KIFQINDVTGE (SEQ ID NO:1648), CEEFC (SEQ IDNO:1649), CEEFSC (SEQ ID NO:1650), CEEFSGC (SEQ ID NO:1651), CLEEFC (SEQID NO:1652), CLEEFSC (SEQ ID NO:1653), CLEEFSGC (SEQ ID NO:1654),CVLEEFC (SEQ ID NO:1655), CVLEEFSC (SEQ ID NO:1656), CVLEEFSGC (SEQ IDNO:1657), CFVLEEFC (SEQ ID NO:1658), CFVLEEFSC (SEQ ID NO:1659),CFVLEEFSGC (SEQ ID NO:1660), CMFVLEEFC (SEQ ID NO:1661), CMFVLEEFSC (SEQID NO:1662), CMFVLEEFSGC (SEQ ID NO:1663), EEEFK (SEQ ID NO:1664),EEEFSK (SEQ ID NO:1665), EEEFSGK (SEQ ID NO:1666), ELEEFK (SEQ IDNO:1667), ELEEFSK (SEQ ID NO:1668), ELEEFSGK (SEQ ID NO:1669), EVLEEFK(SEQ ID NO:1670), EVLEEFSK (SEQ ID NO:1671), EVLEEFSGK (SEQ ID NO:1672),EFVLEEFK (SEQ ID NO:1673), EFVLEEFSK (SEQ ID NO:1674), EFVLEEFSGK (SEQID NO:1675), EMFVLEEFK (SEQ ID NO:1676) EMFVLEEFSK (SEQ ID NO:1677),EMFVLEEFSGK (SEQ ID NO:1678)₁ KEEFD (SEQ ID NO:1679), KEEFSD (SEQ IDNO:1680), KEEFSGD (SEQ ID NO:1681), KLEEFD (SEQ ID NO:1682), KLEEFSD(SEQ ID NO:1683), KLEEFSGD (SEQ ID NO:1684), KVLEEFD (SEQ ID NO:1685),KVLEEFSD (SEQ ID NO:1686), KVLEEFSGD (SEQ ID NO:1687), KFVLEEFD (SEQ IDNO:1688), KFVLEEFSD (SEQ ID NO:1689), KFVLEEFSGD (SEQ ID NO:1690),KMFVLEEFD (SEQ ID NO:1691), KMFVLEEFSD (SEQ ID NO:1692), KMFVLEEFSGD(SEQ ID NO:1693), DEEFK (SEQ ID NO:1694), DEEFSK (SEQ ID NO:1695),DEEFSGK (SEQ ID NO:1696), DLEEFK (SEQ ID NO:1697), DLEEFSK (SEQ IDNO:1698), DLEEFSGK (SEQ ID NO:1699), DVLEEFK (SEQ ID NO:1700), DVLEEFSK(SEQ ID NO:1701), DVLEEFSGK (SEQ ID NO:1702), DFVLEEFK (SEQ ID NO:1703),DFVLEEFSK (SEQ ID NO:1704), DFVLEEFSGK (SEQ ID NO:1705), DMFVLEEFK (SEQID NO:1706), DMFVLEEFSK (SEQ ID NO:1707), DMFVLEEFSGK (SEQ ID NO:1708),KEEFE (SEQ ID NO:1709), KEEFSE (SEQ ID NO:1710), KEEFSGE (SEQ IDNO:1711), KLEEFE (SEQ ID NO:1712), KLEEFSE (SEQ ID NO:1713), KLEEFSGE(SEQ ID NO:1714), KVLEEFE (SEQ ID NO:1715), KVLEEFSE (SEQ ID NO:1716),KVLEEFSGE (SEQ ID NO:1717), KFVLEEFE (SEQ ID NO:1718), KFVLEEFSE (SEQ IDNO:1719), KFVLEEFSGE (SEQ ID NO:1720), KMFVLEEFE (SEQ ID NO:1721),KMFVLEEFSE (SEQ ID NO:1722), KMFVLEEFSGE (SEQ ID NO:1723), EEFSG (SEQ IDNO:1724), LEEFS (SEQ ID NO:1725), LEEFSG (SEQ ID NO:1726), VLEEF (SEQ IDNO:1727), VLEEFS (SEQ ID NO:1728), VLEEFSG (SEQ ID NO:1729), FVLEEF (SEQID NO:1730), FVLEEFS (SEQ ID NO:1731), FVLEEFSG (SEQ ID NO:1732),MFVLEEF (SEQ ID NO:1733), MFVLEEFS (SEQ ID NO:1734) and MFVLEEFSG (SEQID NO:1735).

[0118] Representative cyclic peptides comprising a cadherin-12 CARsequence include: CDETC (SEQ ID NO:1736), CIDETC (SEQ ID NO:1737),CDETTC (SEQ ID NO:1738), CTIDETC (SEQ ID NO:1739), CIDETTC (SEQ IDNO:1740), CTIDETTC (SEQ ID NO:1741), CDETTGC (SEQ ID NO:1742), CIDETTGC(SEQ ID NO:1743), CTIDETTGC (SEQ ID NO:1744), CFTIDETC (SEQ ID NO:1745),CFTIDETTC (SEQ ID NO:1746), CFTIDETTGC (SEQ ID NO:1747), CVFTIDETC (SEQID NO:1748), CVFTIDETTC (SEQ ID NO:1749), CVFTIDETTGC (SEQ ID NO:1750),DDETK (SEQ ID NO:1752), DIDETK (SEQ ID NO:1753), DTIDETK (SEQ IDNO:1754), DFTIDETK (SEQ ID NO:1755), DVFTIDETK (SEQ ID NO:1756),EDETK,(SEQ ID NO:1757), EIDETK (SEQ ID NO:1758), ETIDETK (SEQ IDNO:1759), EFTIDETK (SEQ ID NO:1760), EVFTIDETK (SEQ ID NO:1761), KDETD(SEQ ID NO:1762), KIDETD (SEQ ID NO:1763), KDETTD (SEQ ID NO:1764),KTIDETD (SEQ ID NO:1765), KIDETTD (SEQ ID NO:1766), KTIDETTD (SEQ IDNO:1767), KDETTGD (SEQ ID NO:1768), KIDETTGD (SEQ ID NO:1769), KTIDETTGD(SEQ ID NO:1770), KFTIDETD (SEQ ID NO:1771), KFTIDETTD (SEQ ID NO:1772),KFTIDETTGD (SEQ ID NO:1773), KVFTIDETD (SEQ ID NO:1774), KVFTIDETTD (SEQID NO:1775), KVFTIDETTGD (SEQ ID NO:1776), DDETTK (SEQ ID NO:1751),DIDETTK (SEQ ID NO:1777), DTIDETTK (SEQ ID NO:3934), DFTIDETTK (SEQ IDNO:3935), DVFTIDETTK (SEQ ID NO:3936), DDETTGK (SEQ ID NO:3937),DIDETTGK (SEQ ID NO:3938), DTIDETTGK (SEQ ID NO:3939), DFTIDETTGK (SEQID NO:3940), DVFTIDETTGK (SEQ ID NO:3941), EDETTK (SEQ ID NO:3942),EIDETTK (SEQ ID NO:3943), ETIDETTK (SEQ ID NO:3944), EFTIDETTK (SEQ IDNO:3945), DVFTIDETTK (SEQ ID NO:3946), EDETTGK (SEQ ID NO:3947),EIDETTGK (SEQ ID NO:3948), ETIDETTGK (SEQ ID NO:3949), EFTIDETTGK (SEQID NO:3950), EVFTIDETTGK (SEQ ID NO:3951), IDETT (SEQ ID NO:1778),TIDETT (SEQ ID NO:1779), DETTG (SEQ ID NO:1780), IDETTG (SEQ ID NO:1781)KDETE (SEQ ID NO:1782), KIDETE (SEQ ID NO:1783), KDETTE (SEQ IDNO:1784), KTIDETE (SEQ ID NO:1785), KIDETTE (SEQ ID NO:1786), KTIDETTE(SEQ ID NO:1787), KDETTGE (SEQ ID NO:1788), KIDETTGE (SEQ ID NO:1789),KTIDETTGE (SEQ ID NO:1790), KFTIDETE (SEQ ID NO:1791), KFTIDETTE (SEQ IDNO:1792), KFTIDETTGE (SEQ ID NO:1793), KVFTIDETE (SEQ ID NO:1794),KIFTIDETTE (SEQ ID NO:1795), KVFTIDETTGE (SEQ ID NO:1796), CDPKC (SEQ IDNO:1797), CDPKTC (SEQ ID NO:1798), CDPKTGC (SEQ ID NO:1799), CIDPKC (SEQID NO:1800), CIDPKTC (SEQ ID NO:1801), CIDPKTGC (SEQ ID NO:1802),CSIDPKC (SEQ ID NO:1803), CSIDPKTC (SEQ ID NO:1804), CSIDPKTGC (SEQ IDNO:1805), CFSIDPKC (SEQ ID NO:1806), CFSIDPKTC (SEQ ID NO:1807),CFSIDPKTGC (SEQ ID NO:1808), CYFSIDPKC (SEQ ID NO:1809), CYFSIDPKTC (SEQID NO:1810), CYFSIDPKTGC (SEQ ID NO:1811), EDPKK (SEQ ID NO:1812),EDPKTK (SEQ ID NO:1813), EDPKTGK (SEQ ID NO:1814), EIDPKK (SEQ IDNO:1815), EIDPKTK (SEQ ID NO:1816), EIDPKTGK (SEQ ID NO:1817), ESIDPKK(SEQ ID NO:1818), ESIDPKTK (SEQ ID NO:1819), ESIDPKTGK (SEQ ID NO:1820),EFSIDPKK (SEQ ID NO:1821), EFSIDPKTK (SEQ ID NO:1822), EFSIDPKTGK (SEQID NO:1823), EYFSIDPKK (SEQ ID NO:1824), EYFSIDPKTK (SEQ ID NO:1825),EYFSIDPKTGK (SEQ ID NO:1826)₁ KDPKD (SEQ ID NO:1827), KDPKTD (SEQ IDNO:1828), KDPKTGD (SEQ ID NO:1829), KIDPKD (SEQ ID NO:1830), KIDPKTD(SEQ ID NO:1831), KIDPKTGD (SEQ ID NO:1832), KSIDPKD (SEQ ID NO:1833),KSIDPKTD (SEQ ID NO:1834), KSIDPKTGD (SEQ ID NO:1835), KFSIDPKD (SEQ IDNO:1836), KFSIDPKTD (SEQ ID NO:1837), KFSIDPKTGD (SEQ ID NO:1838),KYFSIDPKD (SEQ ID NO:1839), KYFSIDPKTD (SEQ ID NO:1840), KYFSIDPKTGD(SEQ ID NO:1841), DDPKK (SEQ ID NO:1842), DDPKTK (SEQ ID NO:1843),DDPKTGK (SEQ ID NO:1844), DIDPKK (SEQ ID NO:1845), DIDPKTK (SEQ IDNO:1846), DIDPKTGK (SEQ ID NO:1847), DSIDPKK (SEQ ID NO:1848), DSIDPKTK(SEQ ID NO:1849), DSIDPKTGK (SEQ ID NO:1850), DFSIDPKK (SEQ ID NO:1851),DFSIDPKTK (SEQ ID NO:1852), DFSIDPKTGK (SEQ ID NO:1853), DYFSIDPKK (SEQID NO:1854), DYFSIDPKTK (SEQ ID NO:1855), DYFSIDPKTGK (SEQ ID NO:1856),KDPKE (SEQ ID NO:1857), KDPKTE (SEQ ID NO:1858), KDPKTGE (SEQ IDNO:1859), KIDPKE (SEQ ID NO:1860), KIDPKTE (SEQ ID NO:1861), KIDPKTGE(SEQ ID NO:1862), KSIDPKE (SEQ ID NO:1863), KSIDPKTE (SEQ ID NO:1864),KSIDPKTGE (SEQ ID NO:1865), KFSIDPKE (SEQ ID NO:1866), KFSIDPKTE (SEQ IDNO:1867), KFSIDPKTGE (SEQ ID NO:1868), KYFSIDPKE (SEQ ID NO:1869),KYFSIDPKTE (SEQ ID NO:1870), KYFSIDPKTGE (SEQ ID NO:1871), DPKTG (SEQ IDNO:1872), IDPKT (SEQ ID NO:1873), IDPKTG (SEQ ID NO:1874), SIDPK (SEQ IDNO:1875), SIDPKT (SEQ ID NO:1876), SIDPKTG (SEQ ID NO:1877), FSIDPK (SEQID NO:1878), FSIDPKT (SEQ ID NO:1879), FSIDPKTG (SEQ ID NO:1880),YFSIDPK (SEQ ID NO:1881), YFSIDPKT (SEQ ID NO:1882) and YFSIDPKTG (SEQID NO:1883).

[0119] Representative cyclic peptides comprising a cadherin-14 CARsequence include: CDDTC (SEQ ID NO:1884), CIDDTC (SEQ ID NO:1885),CDDTTC (SEQ ID NO:1886), CIIDDTC (SEQ ID NO:1887), CIDDTTC (SEQ IDNO:1888), CIIDDTTC (SEQ ID NO:1889), CDDTTGC (SEQ ID NO:1890), CIDDTTGC(SEQ ID NO:1891), CIIDDTTGC (SEQ ID NO:1892), CFIIDDTC (SEQ ID NO:1893),CFIIDDTTC (SEQ ID NO:1894), CFIIDDTTGC (SEQ ID NO:1895), CIFIIDDTC (SEQID NO:1896), CIFIIDDTTC (SEQ ID NO:1897), CIFIIDDTTGC (SEQ ID NO:1898),EDDTTK (SEQ ID NO:1899), EIDDTTK (SEQ ID NO:3952), EIIDDTTK (SEQ IDNO:3953), EFIIDDTTK (SEQ ID NO:3954), EIFIIDDTTK (SEQ ID NO:3955),EDDTTGK (SEQ ID NO:3956), EIDDTTGK (SEQ ID NO:3957), EIIDDTTGK (SEQ IDNO:3958), EFIIDDTTGK (SEQ ID NO:3959), EIFIIDDTTGK (SEQ ID NO:3960),DDDTTK (SEQ ID NO:3961), DIDDTTK (SEQ ID NO:3962), DFIIDDTTK (SEQ IDNO:3963), DIFIIDDTTK (SEQ ID NO:3964), DDDTTGK (SEQ ID NO:3965),DIDDTTGK (SEQ ID NO:3966), DIIDDTTGK (SEQ ID NO:3967), DFIIDDTTGK (SEQID NO:3968), DIFIIDDTTGK (SEQ ID NO:3969), DDDTK (SEQ ID NO:1900),DIDDTNK (SEQ ID NO:1901), DIIDDTK (SEQ ID NO:1902), DFIIDDTK (SEQ IDNO:1903), DIFIIDDTK (SEQ ID NO:1904), EDDTK (SEQ ID NO:1905), EIDDTK(SEQ ID NO:1906), EIIDDTK (SEQ ID NO:1907), EFIIDDTK (SEQ ID NO:1908),EIFIIDDTK (SEQ ID NO:1909), KDDTD (SEQ ID NO:1910), KIDDTD (SEQ IDNO:1911), KDDTTD (SEQ ID NO:1912), KIIDDTD (SEQ ID NO:1913), KIDDTTD(SEQ ID NO:1914), KIIDDTTD (SEQ ID NO:1915), KDDTTGD (SEQ ID NO:1916),KIDDTTGD (SEQ ID NO:1917), KIIDDTTGD (SEQ ID NO:1918), KFIIDDTD (SEQ IDNO:1919), KFIIDDTTD (SEQ ID NO:1920), KFIIDDTTGD (SEQ ID NO:1921),KIFIIDDTD (SEQ ID NO:1922), KIFIIDDTTD (SEQ ID NO:1923), KIFIIDDTTGD(SEQ ID NO:1924), DDTT (SEQ ID NO:1925), IDDTT (SEQ ID NO:1926), IIDDTT(SEQ ID NO:1927), DDTTG (SEQ ID NO:1928), IDDTTG (SEQ ID NO:1929) KDDTE(SEQ ID NO:1930), KIDDTE (SEQ ID NO:1931), KDDTTE (SEQ ID NO:1932),KIIDDTE (SEQ ID NO:1933), KIDDTTE (SEQ ID NO:1934), KIIDDTTE (SEQ IDNO:1935), KDDTTGE (SEQ ID NO:1936), KIDDTTGE (SEQ ID NO:1937), KIIDDTTGE(SEQ ID NO:1938), KFIIDDTE (SEQ ID NO:1939), KFIIDDTTE (SEQ ID NO:1940),KFIIDDTTGE (SEQ ID NO:1941), KIFIIDDTE (SEQ ID NO:1942), KIFIIDDTTE (SEQID NO:1943), KIFIIDDTTGE (SEQ ID NO:1944), CDPKC (SEQ ID NO:1945),CVDPKC (SEQ ID NO:1946), CVDPKTC (SEQ ID NO:1947), CVDPKTGC (SEQ IDNO:1948), CSVDPKC (SEQ ID NO:1949), CSVDPKTC (SEQ ID NO:1950), CSVDPKTGC(SEQ ID NO:1951), CFSVDPKC (SEQ ID NO:1952), CFSVDPKTC (SEQ ID NO:1953),CFSVDPKTGC (SEQ ID NO:1954), CYFSVDPKC (SEQ ID NO:1955), CYFSVDPKTC (SEQID NO:1956), CYFSVDPKTGC (SEQ ID NO:1957), CDPKTC (SEQ ID NO:3970),CDPKTGC (SEQ ID NO:3971), CDANC (SEQ ID NO:1958), CDANTC (SEQ IDNO:1959), CDANTGC (SEQ ID NO:1960), CIDANTC (SEQ ID NO:1961), CIDANTGC(SEQ ID NO:1962), CNIDANTC (SEQ ID NO:1963), CNIDANTGC (SEQ ID NO:1964),CFNIDANTC (SEQ ID NO:1965), CFNIDANTGC (SEQ ID NO:1966), CFFNIDANC (SEQID NO:1967), CFFNIDANTC (SEQ ID NO:1968), CFFNIDANTGC (SEQ ID NO:1969),CIDANC (SEQ ID NO:3972), CNIDANC (SEQ ID NO:3973), CFNIDANC (SEQ IDNO:3974), EDPKK (SEQ ID NO:1970), EDPKTK (SEQ ID NO:1971), EDPKTGK (SEQID NO: 1972), EVDPKK (SEQ ID NO: 1973), EVDPKTK (SEQ ID NO: 1974),EVDPKTGK (SEQ ID NO: 1975), ESVDPKK (SEQ ID NO: 1976), ESVDPKTK (SEQ IDNO:1977), ESVDPKTGK (SEQ ID NO:1978), EFSVDPKK (SEQ ID NO:1979),EFSVDPKTK (SEQ ID NO:1980), EFSVDPKTGK (SEQ ID NO:1981), EYFSVDPKK (SEQID NO:1982), EYFSVDPKTK (SEQ ID NO:1983), EYFSVDPKTGK (SEQ ID NO:1984),EDANK (SEQ ID NO:1985), EDANTK (SEQ ID NO:1986), EDANTGK (SEQ IDNO:1987), EIDANTK (SEQ ID NO:1988), EIDANTGK (SEQ ID NO:1989), ENIDANTK(SEQ ID NO:1990), ENIDANTGK (SEQ ID NO:1991), EFNIDANTK (SEQ IDNO:1992), EFNIDANTGK (SEQ ID NO:1993), EFFNIDANK (SEQ ID NO:1994),EFFNIDANTK (SEQ ID NO:1995), EFFNIDANTGK (SEQ ID NO:1996), EIDANK (SEQID NO:3975), ENIDANK (SEQ ID NO:3976), EFNIDANK (SEQ ID NO:3977), KVDPKD(SEQ ID NO:1997), KVDPKTD (SEQ ID NO:1998), KVDPKTGD (SEQ ID NO:1999),KSVDPKD (SEQ ID NO:2000), KSVDPKTD (SEQ ID NO:2001), KSVDPKTGD (SEQ IDNO:2002), KFSVDPKD (SEQ ID NO:2003), KFSVDPKTD (SEQ ID NO:2004),KFSVDPKTGD (SEQ ID NO:2005), KYFSVDPKD (SEQ ID NO:2006), KYFSVDPKTD (SEQID NO:2007), KYFSVDPKTGD (SEQ ID NO:2008), KDPKD (SEQ ID NO:3978),KDPKTD (SEQ ID NO:3979), KDPKTGD (SEQ ID NO:3980), KDAND (SEQ IDNO:3981), KIDAND (SEQ ID NO:3982), KNIDAND (SEQ ID NO:3983), KDANTD (SEQID NO:2009), KDANTGD (SEQ ID NO:2010), KIDANTD (SEQ ID NO:2011),KIDANTGD (SEQ ID NO:2012), KNIDANTD (SEQ ID NO:2013), KNIDANTGD (SEQ IDNO:2014), KFNIDANTD (SEQ ID NO:2015), KFNIDANTGD (SEQ ID NO:2016),KFFNIDAND (SEQ ID NO:2017), KFFNIDANTD (SEQ ID NO:2018), KFFNIDANTGD(SEQ ID NO:2019), DDPKK (SEQ ID NO:2020), DDPKTK (SEQ ID NO:2021),DDPKTGK (SEQ ID NO:2022), DVDPKK (SEQ ID NO:2023), DVDPKTK (SEQ IDNO:2024), DVDPKTGK (SEQ ID NO:2025), DSVDPKK (SEQ ID NO:2026), DSVDPKTK(SEQ ID NO:2027), DSVDPKTGK (SEQ ID NO:2028), DFSVDPKK (SEQ ID NO:2029),DFSVDPKTK (SEQ ID NO:2030), DFSVDPKTGK (SEQ ID NO:2031), DYFSVDPKK (SEQID NO:2032), DYFSVDPKTK (SEQ ID NO:2033), DYFSVDPKTGK (SEQ ID NO:2034),DDANK (SEQ ID NO:2035), DDANTK (SEQ ID NO:2036), DDANTGK (SEQ IDNO:2037), DIDANTK (SEQ ID NO:2038), DIDANTGK (SEQ ID NO:2039), DNIDANTK(SEQ ID NO:2040), DNIDANTGK (SEQ ID NO:2041), DFNIDANTC (SEQ IDNO:2042), DFNIDANTGK (SEQ ID NO:2043), DFFNIDANK (SEQ ID NO:2044),DFFNIDANTK (SEQ ID NO:2045), DFFNIDANTGK (SEQ ID NO:2046), DIDANK (SEQID NO:3984), DNIDANK (SEQ ID NO:3985), DFNIDANK (SEQ ID NO:3986),DFNIDANTK (SEQ ID NO:3987), KDPKE (SEQ ID NO:3988), KDPKTE (SEQ IDNO:3989), KDPKTGE (SEQ ID NO:3990), KVDPKE (SEQ ID NO:2047), KVDPKTE(SEQ ID NO:2048), KVDPKTGE (SEQ ID NO.2049), KSVDPKE (SEQ ID NO:2050),KSVDPKTE (SEQ ID NO:2051), KSVDPKTGE (SEQ ID NO:2052), KFSVDPKE (SEQ IDNO:2053), KFSVDPKTE (SEQ ID NO:2054), KFSVDPKTGE (SEQ ID NO:2055),KYFSVDPKE (SEQ ID NO:2056), KYFSVDPKTE (SEQ ID NO:2057), KYFSVDPKTGE(SEQ ID NO:2058), KDANE (SEQ ID NO:2059), KDANTE (SEQ ID NO:2060),KDANTGE (SEQ ID NO:2061), KIDANTE (SEQ ID NO:2062), KIDANTGE (SEQ IDNO:2063), KNIDANTE (SEQ ID NO:2064), KNIDANTGE (SEQ ID NO:2065),KFNIDANTE (SEQ ID NO:2066), KFNIDANTGE (SEQ ID NO:2067), KFFNIDANE (SEQID NO:2068), KFFNIDANTE (SEQ ID NO:2069), KFFNIDANTGE (SEQ ID NO:2070),KIDANE (SEQ ID NO:3991), KNIDANE (SEQ ID NO:3992), KFNIDANE (SEQ IDNO:3993), VDPKT (SEQ ID NO:2071), VDPKTG (SEQ ID NO:2072), SVDPK (SEQ IDNO:2073), SVDPKT (SEQ ID NO:2074), SVDPKTG (SEQ ID NO:2075), FSVDPK (SEQID NO:2076), FSVDPKT (SEQ ID NO:2077), FSVDPKTG (SEQ ID NO:2078),YFSVDPK (SEQ ID NO:2079), YFSVDPKT (SEQ ID NO:2080), YFSVDPKTG (SEQ IDNO:2081), DANTG (SEQ ID NO:2082), IDANT (SEQ ID NO:2083), IDANTG (SEQ IDNO:2084), NIDANT (SEQ ID NO:2085), NIDANTG (SEQ ID NO:2086), FNIDANT(SEQ ID NO:2087), FNIDANTG (SEQ ID NO:2088), FFNIDAN (SEQ ID NO:2089),FFNIDANT (SEQ ID NO:2090), and FFNIDANTG (SEQ ID NO:2091).

[0120] Representative cyclic peptides comprising a cadherin-15 CARsequence include: CDKFC (SEQ ID NO:2092), CIDKFC (SEQ ID NO:2093),CDKFTC (SEQ ID NO:2094), CSIDKFC (SEQ ID NO:2095), CIDKFTC (SEQ IDNO:2096), CSIDKFTC (SEQ ID NO:2097), CDKFTGC (SEQ ID NO:2098), CIDKFTGC(SEQ ID NO:2099), CSIDKFTGC (SEQ ID NO:2100), CFSIDKFC (SEQ ID NO:2101),CFSIDKFTC (SEQ ID NO:2102), CFSIDKFTGC (SEQ ID NO:2103), CVFSIDKFC (SEQID NO:2104), CVFSIDKFTC (SEQ ID NO:2105), CVFSIDKFTGC (SEQ ID NO:2106),DDKFK (SEQ ID NO:2108), DIDKFK (SEQ ID NO:2109), DSIDKFK (SEQ IDNO:2110), DFSIDKFK (SEQ ID NO:2111), DVFSIDKFK (SEQ ID NO:2112), DDKFTK(SEQ ID NO:2107), DIDKFTK (SEQ ID NO:2133), DSIDKFTK (SEQ ID NO:3994),DFSIDKFTK (SEQ ID NO:3995), DVFSIDKFTK (SEQ ID NO:3996), DDKTGK (SEQ IDNO:3997), DIDKFTGK (SEQ ID NO:3998), DSIDKFTGK (SEQ ID NO:3999),DFSIDKFTGK (SEQ ID NO:4000), DVFSIDKFTGK (SEQ ID NO:4001), EDKFTK (SEQID NO:4002), EIDKFTK (SEQ ID NO:4003), ESIDKFTK (SEQ ID NO:4004),EFSIDKFTK (SEQ ID NO:4005), EVFSIDKFTK (SEQ ID NO:4006), EDKFTGK (SEQ IDNO:4007), EIDKFTGK (SEQ ID NO:4008), EFSIDKFTGK (SEQ ID NO:4009),EVFSIDKFTGK (SEQ ID NO:4010), EDKFK (SEQ ID NO:2113), EIDKFK (SEQ IDNO:2114), ESIDKFK (SEQ ID NO:2115), EFSIDKFK (SEQ ID NO:2116), EVFSIDKFK(SEQ ID NO:2117), KDKFD (SEQ ID NO:2118), KIDKFD (SEQ ID NO:2119),KDKFTD (SEQ ID NO:2120), KSIDKFD (SEQ ID NO:2121), KIDKFTD (SEQ IDNO:2122), KSIDKFTD (SEQ ID NO:2123), KDKFTGD (SEQ ID NO:2124), KIDKFTGD(SEQ ID NO:2125), KSIDKFTGD (SEQ ID NO:2126), KFSIDKFD (SEQ ID NO:2127),KFSIDKFTD (SEQ ID NO:2128), KFSIDKFTGD (SEQ ID NO:2129), KVFSIDKFD (SEQID NO:2130), KVFSIDKFTD (SEQ ID NO:2131), KVFSIDKFTGD (SEQ ID NO:2132),IDKFT (SEQ ID NO:2134), SIDKFT (SEQ ID NO:2135), DKFTG (SEQ ID NO:2136),IDKFTG (SEQ ID NO:2137) KDKFE (SEQ ID NO:2138), KIDKFE (SEQ ID NO:2139),KDKFTE (SEQ ID NO:2140), KSIDKFE (SEQ ID NO:2141), KIDKFTE (SEQ IDNO:2142), KSIDKFTE (SEQ ID NO:2143), KDKFTGE (SEQ ID NO:2144), KIDKFTGE(SEQ ID NO:2145), KSIDKFTGE (SEQ ID NO:2146), KFSIDKFE (SEQ ID NO:2147),KFSIDKFTE (SEQ ID NO:2148), KFSIDKFTGE (SEQ ID NO:2149), KVFSIDKFE (SEQID NO:2150), KIFSIDKFTE (SEQ ID NO:2151), KVFSIDKFTGE (SEQ ID NO:2152),CDELC (SEQ ID NO:2153), CDELTC (SEQ ID NO:2154), CDELTGC (SEQ IDNO:2155), CIDELC (SEQ ID NO:2156), CIDELTC (SEQ ID NO:2157), CIDELTGC(SEQ ID NO:2158), CSIDELC (SEQ ID NO:2159), CSIDELTC (SEQ ID NO:2160),CSIDELTGC (SEQ ID NO:2161), CFSIDELC (SEQ ID NO:2162), CFSIDELTC (SEQ IDNO:2163), CFSIDELTGC (SEQ ID NO:2164), CLFSIDELC (SEQ ID NO:2165),CLFSIDELTC (SEQ ID NO:2166), CLFSIDELTGC (SEQ ID NO:2167), EDELCK (SEQID NO:2168), EDELTK (SEQ ID NO:2169), EDELTGK (SEQ ID NO:2170), EIDELK(SEQ ID NO:2171), EIDELTK (SEQ ID NO:2172), EIDELTGK (SEQ ID NO:2173),ESIDELK (SEQ ID NO:2174), ESIDELTK (SEQ ID NO:2175), ESIDELTGK (SEQ IDNO:2176), EFSIDELK (SEQ ID NO:2177), EFSIDELTK (SEQ ID NO:2178),EFSIDELTGK (SEQ ID NO:2179), ELFSIDELK (SEQ ID NO:2180), ELFSIDELTK (SEQID NO:2181), ELFSIDELTGK (SEQ ID NO:2182), KDELD (SEQ ID NO:2183),KDELTD (SEQ ID NO:2184), KDELTGD (SEQ ID NO:2185), KIDELD (SEQ IDNO:2186), KIDELTD (SEQ ID NO:2187), KIDELTGD (SEQ ID NO:2188), KSIDELD(SEQ ID NO:2189), KSIDELTD (SEQ ID NO:2190), KSIDELTGD (SEQ ID NO:2191),KFSIDELD (SEQ ID NO:2192), KFSIDELTD (SEQ ID NO:2193), KFSIDELTGD (SEQID NO:2194), KLFSIDELD (SEQ ID NO:2195), KLFSIDELTD (SEQ ID NO:2196),KLFSIDELTGD (SEQ ID NO:2197), DDELK (SEQ ID NO:2198), DDELTK (SEQ IDNO:2199), DDELTGK (SEQ ID NO:2200), DIDELK (SEQ ID NO:2201), DIDELTK(SEQ ID NO:2202), DIDELTGK (SEQ ID NO:2203), DSIDELK (SEQ ID NO:2204),DSIDELTK (SEQ ID NO:2205), DSIDELTGK (SEQ ID NO:2206), DFSIDELK (SEQ IDNO:2207), DFSIDELTK (SEQ ID NO:2208), DFSIDELTGK (SEQ ID NO:2209),DLFSIDELK (SEQ ID NO:2210), DLFSIDELTK (SEQ ID NO:2211), DLFSIDELTGK(SEQ ID NO:2212), KDELE (SEQ ID NO:2213), KDELTE (SEQ ID NO:2214),KDELTGE (SEQ ID NO:2215), KIDELE (SEQ ID NO:2216), KIDELTE (SEQ IDNO:2217), KIDELTGE (SEQ ID NO:2218), KSIDELE (SEQ ID NO:2219), KSIDELTE(SEQ ID NO:2220), KSIDELTGE (SEQ ID NO:2221), KFSIDELE (SEQ ID NO:2222),KFSIDELTE (SEQ ID NO:2223), KFSIDELTGE (SEQ ID NO:2224), KLFSIDELE (SEQID NO:2225), KLFSIDELTE (SEQ ID NO:2226), KLFSIDELTGE (SEQ ID NO:2227),DELTG (SEQ ID NO:2228), IDELT (SEQ ID NO:2229), IDELTG (SEQ ID NO:2230),SIDEL (SEQ ID NO:2231), SIDELT (SEQ ID NO:2232), SIDELTG (SEQ IDNO:2233), FSIDEL (SEQ ID NO:2234), FSIDELT (SEQ ID NO:2235), FSIDELTG(SEQ ID NO:2236), LFSIDEL (SEQ ID NO:2237), LFSIDELT (SEQ ID NO:2238)and LFSIDELTG. (SEQ ID NO:2239).

[0121] Representative cyclic peptides comprising a T-cadherin CARsequence include: CNENC (SEQ ID NO:2240), CINENC (SEQ ID NO:2241),CNENTC (SEQ ID NO:2242), CRINENC (SEQ ID NO:2243), CINENTC (SEQ IDNO:2244), CRINENTC (SEQ ID NO:2245), CNENTGC (SEQ ID NO:2246), CINENTGC(SEQ ID NO:2247), CRINENTGC (SEQ ID NO:2248), CFRINENC (SEQ ID NO:2249),CFRINENTC (SEQ ID NO:2250), CFRINENTGC (SEQ ID NO:2251), CIFRINENC (SEQID NO:2252), CIFRINENTC (SEQ ID NO:2253), CIFRINENTGC (SEQ ID NO:2254),DNENK (SEQ ID NO:2255), DINENK (SEQ ID NO:2256), DRINENK (SEQ IDNO:2257), DFRINENK (SEQ ID NO:2258), DIFRINENK (SEQ ID NO:2259), ENENK(SEQ ID NO:2260), EINENK (SEQ ID NO:2261), ERINENK (SEQ ID NO:2262),EFRINENK (SEQ ID NO:2263), EIFRINENK (SEQ ID NO:2264), KNEND (SEQ IDNO:2265), KINEND (SEQ ID NO:2266), KNENTD (SEQ ID NO:2267), KRINEND (SEQID NO:2268), KINENTD (SEQ ID NO:2269), KRINENTD (SEQ ID NO:2270),KNENTGD (SEQ ID NO:2271), KINENTGD (SEQ ID NO:2272), KRINENTGD (SEQ IDNO:2273), KFRINEND (SEQ ID NO:2274), KFRINENTD (SEQ ID NO:2275),KFRINENTGD (SEQ ID NO:2276), KIFRINEND (SEQ ID NO:2277), KIFRINENTD (SEQID NO:2278), KIFRINENTGD (SEQ ID NO:2279), DNENTK (SEQ ID NO:4011),DINENTK (SEQ ID NO:4012), DRINENTK (SEQ ID NO:4013), DFRINENTK (SEQ IDNO:4014), DIFRINENTK (SEQ ID NO:4015), DNENTGK (SEQ ID NO:4016),DINENTGK (SEQ ID NO:4017), DRINENTGK (SEQ ID NO:4018), DFRINENTGK (SEQID NO:4019), DIFRINENTGK (SEQ ID NO:4020), ENENTK (SEQ ID NO:4021),EINENTK (SEQ ID NO:4022), ERINENTK (SEQ ID NO:4023), EFRINENTK (SEQ IDNO:4024), EIFRINENTK (SEQ ID NO:4025), ENENTGK (SEQ ID NO:4026),EINENTGK (SEQ ID NO:4027), ERINENTGK (SEQ ID NO:4028), EFRINENTGK (SEQID NO:4029), EIFRINENTGK (SEQ ID NO:4030), VNENTG (SEQ ID NO:4031),RINENTG (SEQ ID NO:4032), FRINEN (SEQ ID NO:4033), FRINENT (SEQ IDNO:4034), FRINENTG (SEQ ID NO:4035), IFRINEN (SEQ ID NO:4036), IFRINENT(SEQ ID NO:4037), IFRINENTG (SEQ ID NO:4038), VNENT (SEQ ID NO:2280),INENT (SEQ ID NO:2281), RINENT (SEQ ID NO:2282), NENTG (SEQ ID NO:2283),INENTG (SEQ ID NO:2284) KNENE (SEQ ID NO:2285), KINENE (SEQ ID NO:2286),KNENTE (SEQ ID NO:2287), KRINENE (SEQ ID NO:2288), KINENTE (SEQ IDNO:2289), KRINENTE (SEQ ID NO:2290), KNENTGE (SEQ ID NO:2291), KINENTGE(SEQ ID NO:2292), KRINENTGE (SEQ ID NO:2293), KFRINENE (SEQ ID NO:2294),KFRINENTE (SEQ ID NO:2295), KFRINENTGE (SEQ ID NO:2296), KIFRINENE (SEQID NO:2297), KIFRINENTE (SEQ ID NO:2298) and KIFRINENTGE (SEQ IDNO:2299).

[0122] Representative cyclic peptides comprising a PB-cadherin CARsequence include: CEEYC (SEQ ID NO:2300), CEEYTC (SEQ ID NO:2301),CEEYTG (SEQ ID NO:2302), CVEEYC (SEQ ID NO:2303), CVEEYTC (SEQ IDNO:2304), CVEEYTGC (SEQ ID NO:2305), CVVEEYC (SEQ ID NO:2306), CVVEEYTC(SEQ ID NO:2307), CVVEEYTGC (SEQ ID NO:2308), CFVVEEYC (SEQ ID NO:2309),CFVEEYTC (SEQ ID NO:2310), CFVEEYTGC (SEQ ID NO:2311), CFFVVEEYC (SEQ IDNO:2312), CFFVVEEYTC (SEQ ID NO:2313), CFFVVEEYTGC (SEQ ID NO:2314),CLIDELC (SEQ ID NO:2315), CLIDELTC (SEQ ID NO:2316), CLIDELTGC (SEQ IDNO:2317), CFLIDELC (SEQ ID NO:2318), CFLIDELTC (SEQ ID NO:2319),CFLIDELTGC (SEQ ID NO:2320), CIFLIDELC (SEQ ID NO:2321), CIFLIDELTC (SEQID NO:2322), CIFLIDELTGC (SEQ ID NO:2323), CDELC (SEQ ID NO:4039),CDELTC (SEQ ID NO:4040), CDELTGC (SEQ ID NO:4041), CIDELC (SEQ IDNO:4042), CIDELTC (SEQ ID NO:4043), CIDELTGC (SEQ ID NO:4044), CDPKC(SEQ ID NO:4045), CDPKTC (SEQ ID NO:4046), CDPKTGC (SEQ ID NO:4047),CVDPKC (SEQ ID NO:4048), CVDPKTC (SEQ ID NO:4049), CVDPKTGC (SEQ IDNO:4050), CTVDPKC (SEQ ID NO:2324), CTVDPKTC (SEQ ID NO:2325), CTVDPKTGC(SEQ ID NO:2326), CFTVDPKC (SEQ ID NO:2327), CFTVDPKTC (SEQ ID NO:2328),CFTVDPKTGC (SEQ ID NO:2329), CHFTVDPKC (SEQ ID NO:2330), CHFTVDPKTC (SEQID NO:2331), CHFTVDPKTGC (SEQ ID NO:2332), CDADC (SEQ ID NO:2333),CDADTC (SEQ ID NO:2334), CDADTGC (SEQ ID NO:2335), CIDADC (SEQ IDNO:2336), CIDADTC (SEQ ID NO:2337), CIDADTGC (SEQ ID NO:2338), CDIDADC(SEQ ID NO:2339), CDIDADTC (SEQ ID NO:2340), CDIDADTGC (SEQ ID NO:2341),CFDIDADC (SEQ ID NO:2342), CFDIDADTC (SEQ ID NO:2343), CFDIDADTGC (SEQID NO:2344), CIFDIDADC (SEQ ID NO:2345), CIFDIDADTC (SEQ ID NO:2346),CIFDIDADTGC (SEQ ID NO:2347), EEEYK (SEQ ID NO:2348), EEEYTK (SEQ IDNO:2349), EEEYTGK (SEQ ID NO:2350), EVEEYK (SEQ ID NO:2351), EVEEYTK(SEQ ID NO:2352), EVEEYTGK (SEQ ID NO:2353), EVVEEYK (SEQ ID NO:2354),EVVEEYTK (SEQ ID NO:2355), EVVEEYTGK (SEQ ID NO:2356), EFVVEEYK (SEQ IDNO:2357), EFVEEYTK (SEQ ID NO:2358), EFVEEYTGK (SEQ ID NO:2359), EFFVVYK(SEQ ID NO:2360), EFFVVEEYTK (SEQ ID NO:2361), EFFVVEEYTGK (SEQ IDNO:2362), EDELK (SEQ ID NO:2363), EDELTK (SEQ ID NO:2364), EDELTGK (SEQID NO:2365), EIDELK (SEQ ID NO:2366), EIDELTK (SEQ ID NO:2367), EIDELTGK(SEQ ID NO:2368), ELIDELK (SEQ ID NO:2369), ELIDELTK (SEQ ID NO:2370),ELIDELTGK (SEQ ID NO:2371), EFLIDELK (SEQ ID NO:2372), EFLIDELTK (SEQ IDNO:2373), EFLIDELTGK (SEQ ID NO:2374), EIFLIDELK (SEQ ID NO:2375),EIFLIDELTK (SEQ ID NO:2376), EIFLIDELTGK (SEQ ID NO:2377), EDPKK (SEQ IDNO:2378), EDPKTK (SEQ ID NO:2379), EDPKTGK (SEQ ID NO:2380), EVDPKK (SEQID NO:2381), EVDPKTK (SEQ ID NO:2382), EVDPKTGK (SEQ ID NO:2383),ETVDPKK (SEQ ID NO:2384), ETVDPKTK (SEQ ID NO:2385), ETVDPKTGK (SEQ IDNO:2386), EFTVDPKK (SEQ ID NO:2387), EFTVDPKTK (SEQ ID NO:2388),EFTVDPKTGK (SEQ ID NO:2389), EHFTVDPKK (SEQ ID NO:2390), EHFTVDPKTK (SEQID NO:2391), EHFTVDPKTGK (SEQ ID NO:2392), EDADK (SEQ ID NO:2393),EDADTK (SEQ ID NO:2394), EDADTGK (SEQ ID NO:2395), EIDADK (SEQ IDNO:2396), EIDADTK (SEQ ID NO:2397), EIDADTGK (SEQ ID NO:2398), EDIDADK(SEQ ID NO:2399), EDIDADTK (SEQ ID NO:2400), EDIDADTGK (SEQ ID NO:2401),EFDIDADK (SEQ ID NO:2402), EFDIDADTK (SEQ ID NO:2403), EFDIDADTGK (SEQID NO:2404), EIFDIDADK (SEQ ID NO:2405), EIFDIDADTK (SEQ ID NO:2406),EIFDIDADTGK (SEQ ID NO:2407), KEEYD (SEQ ID NO:2408), KEEYTD (SEQ IDNO:2409), KEEYTGD (SEQ ID NO:2410), KVEEYD (SEQ ID NO:2411), KVEEYTD(SEQ ID NO:2412), KVEEYTGD (SEQ ID NO:2413), KVVEEYD (SEQ ID NO:2414),KVVEEYTD (SEQ ID NO:2415), KVVEEYTGD (SEQ ID NO:2416), KFVVEEYD (SEQ IDNO:2417), KFVEEYTD (SEQ ID NO:2418), KFVEEYTGD (SEQ ID NO:2419),KFFVVEEYD (SEQ ID NO:2420), KFFVVEEYTD (SEQ ID NO:2421), KFFVVEEYTGD(SEQ ID NO:2422), KDELD (SEQ ID NO:2423), KDELTD (SEQ ID NO:2424),KDELTGD (SEQ ID NO:2425), KIDELD (SEQ ID NO:2426), KIDELTD (SEQ IDNO:2427), KIDELTGD (SEQ ID NO:2428), KLIDELD (SEQ ID NO:2429), KLIDELTD(SEQ ID NO:2430), KLIDELTGD (SEQ ID NO:2431), KFLIDELD (SEQ ID NO:2432),KFLIDELTD (SEQ ID NO:2433), KFLIDELTGD (SEQ ID NO:2434), KIFLIDELD (SEQID NO:2435), KIFLIDELTD (SEQ ID NO:2436), KIFLIDELTGD (SEQ ID NO:2437),KDPKD (SEQ ID NO:2438), KDPKTD (SEQ ID NO:2439), KDPKTGD (SEQ IDNO:2440), KVDPKD (SEQ ID NO:2441), KVDPKTD (SEQ ID NO:2442), KVDPKTGD(SEQ ID NO:2443), KTVDPKD (SEQ ID NO:2444), KTVDPKTD (SEQ ID NO:2445),KTVDPKTGD (SEQ ID NO:2446), KFTVDPKD (SEQ ID NO:2447), KFTVDPKTD (SEQ IDNO:2448), KFTVDPKTGD (SEQ ID NO:2449), KHFTVDPKD (SEQ ID NO:2450),KHFTVDPKTD (SEQ ID NO:2451), KHFTVDPKTGD (SEQ ID NO:2452), KDADD (SEQ IDNO:2453), KDADTD (SEQ ID NO:2454), KDADTGD (SEQ ID NO:2455), KIDADD (SEQID NO:2456), KIDADTD (SEQ ID NO:2457), KIDADTGD (SEQ ID NO:2458),KDIDADD (SEQ ID NO:2459), KDIDADTD (SEQ ID NO:2460), KDIDADTGD (SEQ IDNO:2461), KFDIDADD (SEQ ID NO:2462), KFDIDADTD (SEQ ID NO:2463),KFDIDADTGD (SEQ ID NO:2464), KIFDIDADD (SEQ ID NO:2465), KIFDIDADTD (SEQID NO:2466), KIFDIDADTGD (SEQ ID NO:2467), DEEYK (SEQ ID NO:2468),DEEYTK (SEQ ID NO:2469), DEEYTGK (SEQ ID NO:2470), DVEEYK (SEQ IDNO:2471), DVEEYTK (SEQ ID NO:2472), DVEEYTGK (SEQ ID NO:2473), DVVEEYK(SEQ ID NO:2474), DVVEEYTK (SEQ ID NO:2475), DVVEEYTGK (SEQ ID NO:2476),DFVVEEYK (SEQ ID NO:2477), DFVEEYTK (SEQ ID NO:2478), DFVEEYTGK (SEQ IDNO:2479), DFFVVEEYK (SEQ ID NO:2480), DFFVVEEYTK, (SEQ ID NO:2481),DFFVVEEYTGK (SEQ ID NO:2482), DDELK (SEQ ID NO:2483), DDELTK (SEQ IDNO:2484), DDELTGK (SEQ ID NO:2485), DIDELK (SEQ ID NO:2486), DIDELTK(SEQ ID NO:2487), DIDELTGK (SEQ ID NO:2488), DLIDELK (SEQ ID NO:2489),DLIDELTK (SEQ ID NO:2490), DLIDELTGK (SEQ ID NO:2491), DFLIDELK (SEQ IDNO:2492), DFLIDELTK (SEQ ID NO:2493), DFLIDELTGK (SEQ ID NO:2494),DIFLIDELK (SEQ ID NO:2495), DIFLIDELTK (SEQ ID NO:2496), DIFLIDELTGK(SEQ ID NO:2497), DDPKK (SEQ ID NO:2498), DDPKTK (SEQ ID NO:2499),DDPKTGK (SEQ ID NO:2500), DVDPKK (SEQ ID NO:2501), DVDPKYK (SEQ IDNO:2502), DVTPKTGK (SEQ ID NO:2503), DTVDPKK (SEQ ID NO:2504), DTVDPKTK(SEQ ID NO:2505), DTVDPKTGK (SEQ ID NO:2506), DFTVDPKK (SEQ ID NO:2507),DFTVDPKTK (SEQ ID NO:2508), DFTVDPKTGK (SEQ ID NO:2509), DHFTVDPKK (SEQID NO:2510), DHFTVDPKTK (SEQ ID NO:2511), DHFTVDPKTGK (SEQ ID NO:2512),DDADK (SEQ ID NO:2513), DDADTK (SEQ ID NO:2514), DDADTGK (SEQ IDNO:2515), DIDADK (SEQ ID NO:2516), DIDADTK (SEQ ID NO:2517), DIDADTGK(SEQ ID NO:2518), DDIDADK (SEQ ID NO:2519), DDIDADTK (SEQ ID NO:2520),DDIDADTGK (SEQ ID NO:2521), DFDIDADK (SEQ ID NO:2522), DFDIDADTK (SEQ IDNO:2523), DFDIDADTGK (SEQ ID NO:2524), DIFDIDADK (SEQ ID NO:2525),DIFDIDADTK (SEQ ID NO:2526), DIFDIDADTGK (SEQ ID NO:2527), KEEYE (SEQ IDNO:2528), KEEYTE (SEQ ID NO:2529), KEEYTGE (SEQ ID NO:2530), KVEEYE (SEQID NO:2531), KVEEYTE (SEQ ID NO:2532), KVEEYTGE (SEQ ID NO:2533),KVVEEYE (SEQ ID NO:2534), KVVEEYTE (SEQ ID NO:2535), KVVEEYTGE (SEQ IDNO:2536), KFVVEEYE (SEQ ID NO:2537), KFVEEYTE (SEQ ID NO:2538),KFVEEYTGE (SEQ ID NO:2539), KFFVVEEYE (SEQ ID NO:2546), KFFVVEEYTE (SEQID NO:2541), KFFVVEEYTGE (SEQ ID NO:2542), KDELE (SEQ ID NO:2543),KDELTE (SEQ ID NO:2544), KDELTGE (SEQ ID NO:2545), KIDELE (SEQ IDNO:2546), KIDELTE (SEQ ID NO:2547), KIDELTGE (SEQ ID NO:2548), KLIDELE(SEQ ID NO:2549), KLIDELTE (SEQ ID NO:2550), KLIDELTGE (SEQ ID NO:2551),KFLIDELE (SEQ ID NO:2552), KFLIDELTE (SEQ ID NO:2553), KFLIDELTGE (SEQID NO:2554), KIFLIDELE (SEQ ID NO:2555), KIFLIDELTE (SEQ ID NO:2556),KIFLIDELTGE (SEQ ID NO:2557), KDPKE (SEQ ID NO:2558), KDPKTE (SEQ IDNO:2559), KDPKTGE (SEQ ID NO:2560), KVDPKE (SEQ ID NO:2561), KVDPKTE(SEQ ID NO:2562), KDPKTGE (SEQ ID NO:2563), KTVDPKE (SEQ ID NO:2564),KTVDPKTE (SEQ ID NO:2565), KTVDPKTGE (SEQ ID NO:2566), KFTVDPKE (SEQ IDNO:2567), KFTVDPKTE (SEQ ID NO:2568), KFTVDPKTGE (SEQ ID NO:2569),KHFTVDPKE (SEQ ID NO:2570), KHFTVDPKTE (SEQ ID NO:2571), KHFTVDPKTGE(SEQ ID NO:2572), KDADE (SEQ ID NO:2573), KDADTE (SEQ ID NO:2574),KDADTGE (SEQ ID NO:2575), KIDADE (SEQ ID NO:2576), KIDADTE (SEQ IDNO:2577), KIDADTGE (SEQ ID NO:2578), KDIDADE (SEQ ID NO:2579), KDIDADTE(SEQ ID NO:2580), KDIDADTGE (SEQ ID NO:2581), KFDIDADE (SEQ ID NO:2582),KFDIDADTE (SEQ ID NO:2583), KFDIDADTGE (SEQ ID NO:2584), KIFDIDADE (SEQID NO:2585), KIFDIDADTE (SEQ ID NO:2586), KIFDIDADTGE (SEQ ID NO:2587),VEEYT (SEQ ID NO:2588), VEEYTG (SEQ ID NO:2589), VVEEY (SEQ ID NO:2590),VVEEYT (SEQ ID NO:2591), VVEEYTG (SEQ ID NO:2592), FVVEEY (SEQ IDNO:2593), FVEEYT (SEQ ID NO:2594), FVEEYTG (SEQ ID NO:2595), FFVVEEY(SEQ ID NO:2596), FFVVEEYT (SEQ ID NO:2597), FFVVEEYTG (SEQ ID NO:2598),LIDEL (SEQ ID NO:2599), LIDELT (SEQ ID NO:2600), LIDELTG (SEQ IDNO:2601), FLIDEL (SEQ ID NO:2602), FLIDELT (SEQ ID NO:2603), FLIDELTG(SEQ ID NO:2604), IFLIDEL (SEQ ID NO:2605), IFLIDELT (SEQ ID NO:2606),IFLIDELTG (SEQ ID NO:2607), TVDPK (SEQ ID NO:2608), TVDPKT (SEQ IDNO:2609), TVDPKTG (SEQ ID NO:2610), FTVDPK (SEQ ID NO:2611), FTVDPKT(SEQ ID NO:2612), FTVDPKTG (SEQ ID NO:2613), HFTVDPK (SEQ ID NO:2614),HFTVDPKT (SEQ ID NO:2615), HFTVDPKTG (SEQ ID NO:2616), DADTG (SEQ IDNO:2617), IDADT (SEQ ID NO:2618), IDADTG (SEQ ID NO:2619), DIDAD (SEQ IDNO:2620), DIDADT (SEQ ID NO:2621), DIDADTG (SEQ ID NO:2622), FDIDAD (SEQID NO:2623), FDIDADT (SEQ ID NO:2624), FDIDADTG (SEQ ID NO:2625),IFDIDAD (SEQ ID NO:2626), IFDIDADT (SEQ ID NO:2627) and IFDIDADTG (SEQID NO:2628).

[0123] Representative cyclic peptides comprising a LI-cadherin CARsequence include: CNNKC (SEQ ID NO:2629), CNNKTC (SEQ ID NO:2630),CNNKTGC (SEQ ID NO:2631), CINNKC (SEQ ID NO:2632), CINNKTC (SEQ IDNO:2633), CINNKTGC (SEQ ID NO:2634), CQINNKC (SEQ ID NO:2635), CQINNKTC(SEQ ID NO:2636), CQINNKTGC (SEQ ID NO:2637), CFQINNKC (SEQ ID NO:2638),CFQINNKTC (SEQ ID NO:2639), CFQINNKTGC (SEQ ID NO:2640), CYFQINNKC (SEQID NO:2641), CYFQINNKTC (SEQ ID NO:2642), CYFQINNKTGC (SEQ ID NO:2643),ENNKK (SEQ ID NO:2644), ENNKTK (SEQ ID NO:2645), ENNKTGK (SEQ IDNO:2646), EINNKK (SEQ ID NO:2647), EINNKTK (SEQ ID NO:2648), EINNKTGK(SEQ ID NO:2649), EQINNKK (SEQ ID NO:2650), EQINNKTK (SEQ ID NO:2651),EQINNKTGK (SEQ ID NO:2652), EFQINNKK (SEQ ID NO:2653), EFQINNKTK (SEQ IDNO:2654), EFQINNKTGK (SEQ ID NO:2655), EYFQINNKK (SEQ ID NO:2656),EYFQINNKTK (SEQ ID NO:2657), EYFQINNKTGK (SEQ ID NO:2658), KNNKD (SEQ IDNO:2659), KNNKTD (SEQ ID NO:2660), KNNKTGD (SEQ ID NO:2661), KINNKD (SEQID NO:2662), KINNKTD (SEQ ID NO:2663), KINNKTGD (SEQ ID NO:2664),KQINNKD (SEQ ID NO:2665), KQINNKTD (SEQ ID NO:2666), KQINNKTGD (SEQ IDNO:2667), KFQINNKD (SEQ ID NO:2668), KFQINNKTD (SEQ ID NO:2669),KFQINNKTGD (SEQ ID NO:2670), KYFQINNKD (SEQ ID NO:2671), KYFQINNKTD (SEQID NO:2672), KYFQINNKTGD (SEQ ID NO:2673), DNNKK (SEQ ID NO:2674),DNNKTK (SEQ ID NO:2675), DNNKTGK (SEQ ID NO:2676), DINNKK (SEQ IDNO:2677), DINNKTK (SEQ ID NO:2678), DINNKTGK (SEQ ID NO:2679), DQINNKK(SEQ ID NO:2680), DQINNKTK (SEQ ID NO:2681), DQINNKTGK (SEQ ID NO:2682),DFQINNKK (SEQ ID NO:2683), DFQINNKTK (SEQ ID NO:2684), DFQINNKTGK (SEQID NO:2685), DYFQINNKK (SEQ ID NO:2686), DYFQINNKTK (SEQ ID NO:2687),DYFQINNKTGK (SEQ ID NO:2688), KNNKE (SEQ ID NO:2689), KNNKTE (SEQ IDNO:2690), KNNKTGE (SEQ ID NO:2691), KINNKE (SEQ ID NO:2692), KINNKTE(SEQ ID NO:2693), KINNKTGE (SEQ ID NO:2694), KQINNKE (SEQ ID NO:2695),KQINNKTE (SEQ ID NO:2696), KQINNKTGE (SEQ ID NO:2697), KFQINNKE (SEQ IDNO:2698), KFQINNKTE (SEQ ID NO:2699), KFQINNKTGE (SEQ ID NO:2700),KYFQINNKE (SEQ ID NO:2701), KYFQINNKTE (SEQ ID NO:2702), KYFQINNKTGE(SEQ ID NO:2703), NNKTG (SEQ ID NO:2704), INNKT (SEQ ID NO:2705), INNKTG(SEQ ID NO:2706), QINNK (SEQ ID NO:2707), QINNKT (SEQ ID NO:2708),QINNKTG (SEQ ID NO:2709), FQINNK (SEQ ID NO:2710), FQINNKT (SEQ IDNO:2711), FQINNKTG (SEQ ID NO:2712), YFQINNK (SEQ ID NO:2713), YFQINNKT(SEQ ID NO:2714) and YFQINNKTG (SEQ ID NO:2715).

[0124] Representative cyclic peptides comprising a protocadherin CARsequence include: CDLVC (SEQ ID NO:2716), CDLVTC (SEQ ID NO:2717),CDLVTGC (SEQ ID NO:2718), CLDLVC (SEQ ID NO:2719), CLDLVTC (SEQ IDNO:2720), CLDLVTGC (SEQ ID NO:2721), CALDLVC (SEQ ID NO:2722), CALDLVTC(SEQ ID NO:2723), CALDLVTGC (SEQ ID NO:2724), CFALDLVC (SEQ ID NO:2725),CFALDLVTC (SEQ ID NO:2726), CFALDLVTGC (SEQ ID NO:2727), CLFALDLVC (SEQID NO:2728), CLFALDLVTC (SEQ ID NO:2729), CLFALDLVTGC (SEQ ID NO:2730),CNRDC (SEQ ID NO:2731), CNRDNC (SEQ ID NO:2732), CNRDNGC (SEQ IDNO:2733), CINRDC (SEQ ID NO:2734), CINRDNC (SEQ ID NO:2735), CINRDNGC(SEQ ID NO:2736), CTINRDC (SEQ ID NO:2737), CTINRDNC (SEQ ID NO:2738),CTINRDNGC (SEQ ID NO:2739), CFTINRDC (SEQ ID NO:2740), CFTINRDNC (SEQ IDNO:2741), CFTINRDNGC (SEQ ID NO:2742), CYFTINRDC (SEQ ID NO:2743),CYFTINRDNC (SEQ ID NO:2744), CYFTINRDNGC (SEQ ID NO:2745), CDPSC (SEQ IDNO:2746), CDPSSC (SEQ ID NO:2747), CDPSSGC (SEQ ID NO:2748), CIDPSC (SEQID NO:2749), CIDPSSC (SEQ ID NO:2750), CIDPSSGC (SEQ ID NO:2751),CEIDPSC (SEQ ID NO:2752), CEIDPSSC (SEQ ID NO:2753), CEIDPSSGC (SEQ IDNO:2754), CFEIDPSC (SEQ ID NO:2755), CFEIDPSSC (SEQ ID NO:2756),CEIDPSSGC (SEQ ID NO:2757), CFEIDPSC (SEQ ID NO:2758), CFEIDPSSC (SEQ IDNO:2759), CFEIDPSSGC (SEQ ID NO:2760), CLFEIDPSC (SEQ ID NO:2761),CLFEIDPSSC (SEQ ID NO:2762), CLFEIDPSSGC (SEQ ID NO:2763), EDLVK (SEQ IDNO:2764), EDLVTK (SEQ ID NO:2765), EDLVTGK (SEQ ID NO:2766), ELDLVK (SEQID NO:2767), ELDLVTK (SEQ ID NO:2768), ELDLVTGK (SEQ ID NO:2769),EALDLVK (SEQ ID NO:2770), EALDLVTK (SEQ ID NO:2771), EALDLVTGK (SEQ IDNO:2772), EFALDLVK (SEQ ID NO:2773), EFALDLVTK (SEQ ID NO:2774),EFALDLVTGK (SEQ ID NO:2775), ELFALDLVK (SEQ ID NO:2776), ELFALDLVTK (SEQID NO:2777), ELFALDLVTGK (SEQ ID NO:2778), ENRDK (SEQ ID NO:2779),ENRDNK (SEQ ID NO:2780), ENRDNGK (SEQ ID NO:2781), EINRDK (SEQ IDNO:2782), EINRDNK (SEQ ID NO:2783), EINRDNGK (SEQ ID NO:2784), ETINRDK(SEQ ID NO:2785), ETINRDNK (SEQ ID NO:2786), ETINRDNGK (SEQ ID NO:2787),EFTINRDK (SEQ ID NO:2788), EFTINRDNK (SEQ ID NO:2789), EFTINRDNGK (SEQID NO:2790), EYFTINRDK (SEQ ID NO:2791), EYFTINRDNK (SEQ ID NO:2792),EYFTINRDNGK (SEQ ID NO:2793), EDPKK (SEQ ID NO:2794), EDPKTK (SEQ IDNO:2795), EDPKTGK (SEQ ID NO:2796), EIDPKK (SEQ ID NO:2797), EIDPKTK(SEQ ID NO:2798), EIDPKTGK (SEQ ID NO:2799), ESIDPKK (SEQ ID NO:2800),ESIDPKTK (SEQ ID NO:2801), ESIDPKTGK (SEQ ID NO:2802), EFSIDPKK (SEQ IDNO:2803), EFSIDPKTK (SEQ ID NO:2804), EFSIDPKTGK (SEQ ID NO:2805),ELFSIDPKK (SEQ ID NO:2806), ELFSIDPKTK (SEQ ID NO:2807), ELFSIDPKTGK(SEQ ID NO:2808), EDPSK (SEQ ID NO:2809), EDPSSK (SEQ ID NO:2810),EDPSSGK (SEQ ID NO:2811), EIDPSK (SEQ ID NO:2812), EIDPSSK (SEQ IDNO:2813), EIDPSSGK (SEQ ID NO:2814), EEIDPSK (SEQ ID NO:2815), EEIDPSSK(SEQ ID NO:2816), EEIDPSSGK (SEQ ID NO:2817), EFEIDPSK (SEQ ID NO:2818),EFEIDPSSK (SEQ ID NO:2819), EEIDPSSGK (SEQ ID NO:2820), EFEIDPSK (SEQ IDNO:2821), EFEIDPSSK (SEQ ID NO:2822), EFEIDPSSGK (SEQ ID NO:2823),ELFEIDPSK (SEQ ID NO:2824), ELFEIDPSSK (SEQ ID NO:2825), ELFEIDPSSGK(SEQ ID NO:2826), KDLVD (SEQ ID NO:2827), KDLVTD (SEQ ID NO:2828),KDLVTGD (SEQ ID NO:2829), KLDLVD (SEQ ID NO:2830), KLDLVTD (SEQ IDNO:2831), KLDLVTGD (SEQ ID NO:2832), KALDLVD (SEQ ID NO:2833), KALDLVTD(SEQ ID NO:2834), KALDLVTGD (SEQ ID NO:2835), KFALDLVD (SEQ ID NO:2836),KFALDLVTD (SEQ ID NO:2837), KFALDLVTGD (SEQ ID NO:2838), KLFALDLVD (SEQID NO:2839), KLFALDLVTD (SEQ ID NO:2840), KLFALDLVTGD (SEQ ID NO:2841),KNRDD (SEQ ID NO:2842), KNRDND (SEQ ID NO:2843), KNRDNGD (SEQ IDNO:2844), KINRDD (SEQ ID NO:2845), KINRDND (SEQ ID NO:2846), KINRDNGD(SEQ ID NO:2847), KTINRDD (SEQ ID NO:2848), KTINRDND (SEQ ID NO:2849),KTINRDNGD (SEQ ID NO:2850), KFTINRDD (SEQ ID NO:2851), KFTINRDND (SEQ IDNO:2852), KFTINRDNGD (SEQ ID NO:2853), KYFTINRDD (SEQ ID NO:2854),KYFTINRDND (SEQ ID NO:2855), KYFTINRDNGD (SEQ ID NO:2856), KDPKD (SEQ IDNO:2857), KDPKTD (SEQ ID NO:2858), KDPKTGD (SEQ ID NO:2859), KIDPKD (SEQID NO:2860), KIDPKTD (SEQ ID NO:2861), KIDPKTGD (SEQ ID NO:2862),KSIDPKD (SEQ ID NO:2863), KSIDPKTD (SEQ ID NO:2864), KSIDPKTGD (SEQ IDNO:2865), KFSIDPKD (SEQ ID NO:2866), KFSIDPKTD (SEQ ID NO:2867),KFSIDPKTGD (SEQ ID NO:2868), KLFSIDPKD (SEQ ID NO:2869), KLFSIDPKTD (SEQID NO:2870), KLFSIDPKTGD (SEQ ID NO:2871), KDPSD (SEQ ID NO:2872),KDPSSD (SEQ ID NO:2873), KDPSSGD (SEQ ID NO:2874), KIDPSD (SEQ IDNO:2875), KIDPSSD (SEQ ID NO:2876), KIDPSSGD (SEQ ID NO:2877), KEIDPSD(SEQ ID NO:2878), KEIDPSSD (SEQ ID NO:2879), KEIDPSSGD (SEQ ID NO:2880),KFEIDPSD (SEQ ID NO:2881), KFEIDPSSD (SEQ ID NO:2882), KFEIDPSSGD (SEQID NO:2886), KLFEIDPSD (SEQ ID NO:2887), KLFEIDPSSD (SEQ ID NO:2888),KLFEIDPSSGD (SEQ ID NO:2889), KDLVE (SEQ ID NO:2890), KDLVTE (SEQ IDNO:2891), KDLVTGE (SEQ ID NO:2892), KLDLVE (SEQ ID NO:2893), KLDLVTE(SEQ ID NO:2894), KLDLVTGE (SEQ ID NO:2895), KALDLVE (SEQ ID NO:2896),KALDLVTE (SEQ ID NO:2897), KALDLVTGE (SEQ ID NO:2898), KFALDLVE (SEQ IDNO:2899), KFALDLVTE (SEQ ID NO:2900), KFALDLVTGE (SEQ ID NO:2901),KLFALDLVE (SEQ ID NO:2902), KLFALDLVTE (SEQ ID NO:2903), KLFALDLVTGE(SEQ ID NO:2904), KNRDE (SEQ ID NO:2905), KNRDNE (SEQ ID NO:2906),KNRDNGE (SEQ ID NO:2907), KINRDE (SEQ ID NO:2908), KINRDNE (SEQ IDNO:2909), KINRDNGE (SEQ ID NO:2910), KTINRDE (SEQ ID NO:2911), KTINRDNE(SEQ ID NO:2912), KTINRDNGE (SEQ ID NO:2913), KFTINRDE (SEQ ID NO:2914),KFTINRDNE (SEQ ID NO:2915), KFTINRDNGE (SEQ ID NO:2916), KYFTINRDE (SEQID NO:2917), KYFTINRDNE (SEQ ID NO:2918), KYFTINRDNGE (SEQ ID NO:2919),KDPKE (SEQ ID NO:2920), KDPKTE (SEQ ID NO:2921), KDPKTGE (SEQ IDNO:2922), KIDPKE (SEQ ID NO:2923), KIDPKTE (SEQ ID NO:2924), KIDPKTGE(SEQ ID NO:2925), KSIDPKE (SEQ ID NO:2926), KSIDPKTE (SEQ ID NO:2927),KSIDPKTGE (SEQ ID NO:2928), KFSIDPKE (SEQ ID NO:2929), KFSIDPKTE (SEQ IDNO:2930), KFSIDPKTGE (SEQ ID NO:2931), KLFSIDPKE (SEQ ID NO:2932),KLFSIDPKTE (SEQ ID NO:2933), KLFSIDPKTGE (SEQ ID NO:2934), KDPSE (SEQ IDNO:2935), KDPSSE (SEQ ID NO:2936), KDPSSGE (SEQ ID NO:2937), KIDPSE (SEQID NO:2938), KIDPSSE (SEQ ID NO:2939), KIDPSSGE (SEQ ID NO:2940),KEIDPSE (SEQ ID NO:2941), KEIDPSSE (SEQ ID NO:2942), KEIDPSSGE (SEQ IDNO:2943), KFEIDPSE (SEQ ID NO:2944), KFEIDPSSE (SEQ ID NO:2945),KFEIDPSSGE (SEQ ID NO:2949), KLFEIDPSE (SEQ ID NO:2950), KLFEIDPSSE (SEQID NO:2951), KLFEIDPSSGE (SEQ ID NO:2952), DDLVK (SEQ ID NO:2953),DDLVTK (SEQ ID NO:2954), DDLVTGK (SEQ ID NO:2955), DLDLVK (SEQ IDNO:2956), DLDLVTK (SEQ ID NO:2957), DLDLVTGK (SEQ ID NO:2958), DALDLVK(SEQ ID NO:2959), DALDLVTK (SEQ ID NO:2960), DALDLVTGK (SEQ ID NO:2961),DFALDLVK (SEQ ID NO:2962), DFALDLVTK (SEQ ID NO:2963), DFALDLVTGK (SEQID NO:2964), DLFALDLVK (SEQ ID NO:2965), DLFALDLVTK (SEQ ID NO:2966),DLFALDLVTGK (SEQ ID NO:2967), DNRDK (SEQ ID NO:2968), DNRDNK (SEQ IDNO:2969), DNRDNGK (SEQ ID NO:2970), DINRDK (SEQ ID NO:2971), DINRDNK(SEQ ID NO:2972), DINRDNGK (SEQ ID NO:2973), DTINRDK (SEQ ID NO:2974),DTINRDNK (SEQ ID NO:2975), DTINRDNGK (SEQ ID NO:2976), DFTINRDK (SEQ IDNO:2977), DFTINRDNK (SEQ ID NO:2978), DFTINRDNGK (SEQ ID NO:2979),DYFTINRDK (SEQ ID NO:2980), DYFTINRDNK (SEQ ID NO:2981), DYFTINRDNGK(SEQ ID NO:2982), DDPKK (SEQ ID NO:2983), DDPKTK (SEQ ID NO:2984),DDPKTGK (SEQ ID NO:2985), DIDPKK (SEQ ID NO:2986), DIDPKTK (SEQ IDNO:2987), DIDPKTGD (SEQ ID NO:2988), DSIDPKK (SEQ ID NO:2989), DSIDPKTK(SEQ ID NO:2990), DSIDPKTGK (SEQ ID NO:2991), DFSIDPKK (SEQ ID NO:2992),DFSIDPKTK (SEQ ID NO:2993), DFSIDPKTGK (SEQ ID NO:2994), DLFSIDPKK (SEQID NO:2995), DLFSIDPKTK (SEQ ID NO:2996), DLFSIDPKTGK (SEQ ID NO:2997),DDPSK (SEQ ID NO:2998), DDPSSK (SEQ ID NO:2999), DDPSSGK (SEQ IDNO:3000), DIDPSK (SEQ ID NO:3001), DIDPSSK (SEQ ID NO:3002), DIDPSSGK(SEQ ID NO:3003), DEIDPSK (SEQ ID NO:3004), DEIDPSSK (SEQ ID NO:3005),DEIDPSSGK (SEQ ID NO:3006), DFEIDPSK (SEQ ID NO:3007), DFEIDPSSK (SEQ IDNO:3008), DFEIDPSSGK (SEQ ID NO:3012), DLFEIDPSK (SEQ ID NO:3013),DLFEIDPSSK (SEQ ID NO:3014), DLFEIDPSSGK (SEQ ID NO:3015), DLVTG (SEQ IDNO:3016), LDLVT (SEQ ID NO:3017), LDLVTG (SEQ ID NO:3018), ALDLV (SEQ IDNO:3019), ALDLVT (SEQ ID NO:3020), ALDLVTG (SEQ ID NO:3021), FALDLV (SEQID NO:3022), FALDLVTC (SEQ ID NO:3023), FALDLVTG (SEQ ID NO:3024),LFALDLV (SEQ ID NO:3025), LFALDLVT (SEQ ID NO:3026), LFALDLVTG (SEQ IDNO:3027), NRDNG (SEQ ID NO:3028), INRDN (SEQ ID NO:3029), INRDNG (SEQ IDNO:3030), TINRD (SEQ ID NO:3031), TINRDN (SEQ ID NO:3032), TINRDNG (SEQID NO:3033), FTINRD (SEQ ID NO:3034), FTINRDN (SEQ ID NO:3035), FTINRDNG(SEQ ID NO:3036), YFTINRD (SEQ ID NO:3037), YFTINRDN (SEQ ID NO:3038),YFTINRDNG (SEQ ID NO:3039), DPKTG (SEQ ID NO:3040), IDPKT (SEQ IDNO:3041), IDPKTG (SEQ ID NO:3042), SIDPK (SEQ ID NO:3043), SIDPKT (SEQID NO:3044), SIDPKTG (SEQ ID NO:3045), FSIDPK (SEQ ID NO:3046), FSIDPKT(SEQ ID NO:3047), FSIDPKTG (SEQ ID NO:3048), LFSIDPK (SEQ ID NO:3049),LFSIDPKT (SEQ ID NO:3050), LFSIDPKTG (SEQ ID NO:3051), DPSSG (SEQ IDNO:3052), IDPSS (SEQ ID NO:3053), IDPSSG (SEQ ID NO:3054), EIDPSS (SEQID NO:3056), EIDPSSG (SEQ ID NO:3057), FEIDPS (SEQ ID NO:3058), FEIDPSS(SEQ ID NO:3059), EIDPSSG (SEQ ID NO:3060), FEIDPS (SEQ ID NO:3061),FEIDPSSG (SEQ ID NO:3062), LFEIDPS (SEQ ID NO:3063),

[0125] LFEIDPSS (SEQ ID NO:3064) and LFEIDPSSG (SEQ ID NO.3065).

[0126] Representative cyclic peptides comprising a desmoglein CARsequence include: CNQKC (SEQ ID NO:3066), CNQKTC (SEQ ID NO:3067),CNQKTGC (SEQ ID NO:3068), CINQKC (SEQ ID NO:3069), CINQKTC (SEQ IDNO:3070), CINQKTGC (SEQ ID NO:3071), CVINQKC (SEQ ID NO:3072), CVINQKTC(SEQ ID NO:3073), CVINQKTGC (SEQ ID NO:3074), CFVINQKC (SEQ ID NO:3075),CFVINQKTC (SEQ ID NO:3076), CFVINQKTGC (SEQ ID NO:3077), CIFVINQKC (SEQID NO:3078), CIFVINQKTC (SEQ ID NO:3079), CIFVINQKTGC (SEQ ID NO:3080),CNRNC (SEQ ID NO:3081), CNRNTC (SEQ i5 ID NO:3082), CNRNTGC (SEQ IDNO:3083), CINRNC (SEQ ID NO:3084), CINRNTC (SEQ ID NO:3085), CINRNTGC(SEQ ID NO:3086), CIINRNC (SEQ ID NO:3087), CIINRNTC (SEQ ID NO:3088),CIINRNTGC (SEQ ID NO:3089), CFIINRNC (SEQ ID NO:3090), CFIINRNTC (SEQ IDNO:3091), CFIINRNTGC (SEQ ID NO:3092), CMFIINRNC (SEQ ID NO:3093),CMFIINRNTC (SEQ ID NO:3094), CMFIINRNTGC (SEQ ID NO:3095), CNKDC (SEQ IDNO:3096), CNKDTC (SEQ ID NO:3097), CNKDTGC (SEQ ID NO:3098), CLNKDC (SEQID NO:3099), CLNKDTC (SEQ ID NO:3100), CLNKDTGC (SEQ ID NO:3101),CYLNKDC (SEQ ID NO:3102), CYLNKDTC (SEQ ID NO:3103), CYLNKDTGC (SEQ IDNO:3104), CFYLNKDC (SEQ ID NO:3105), CFYLNKDTC (SEQ ID NO:3106),CFYLNKDTGC (SEQ ID NO:3107), CVFYLNKDC (SEQ ID NO:3108), CVFYLNKDTC (SEQID NO:3109), CVFYLNKDTGC (SEQ ID NO:3110), ENQKK (SEQ ID NO:3111),ENQKTK (SEQ ID NO:3112), ENQKTGK (SEQ ID NO:3113), EINQKK (SEQ IDNO:3114), EINQKTK (SEQ ID NO:3115), EINQKTGK (SEQ ID NO:3116), EVINQKK(SEQ ID NO:3117), EVINQKTK (SEQ ID NO:3118), EVINQKTGK (SEQ ID NO:3119),EFVINQKK (SEQ ID NO:3120), EFVINQKTK (SEQ ID NO:3121), EFVINQKTGK (SEQID NO:3122), EIFVINQKK (SEQ ID NO:3123), EIFVINQKTK (SEQ ID NO:3124),EIFVINQKTGK (SEQ ID NO:3125), ENRNK (SEQ ID NO:3126), ENRNTK (SEQ IDNO:3127), ENRNTGK (SEQ ID NO:3128), EINRNK (SEQ ID NO:3129), EINRNTK(SEQ ID NO:3130), EINRNTGK (SEQ ID NO:3131), EIINRNK (SEQ ID NO:3132),EIINRNTK (SEQ ID NO:3133), EIINRNTGK (SEQ ID NO:3134), EFIINRNK (SEQ IDNO:3135), EFIINRNTK (SEQ ID NO:3136), EFIINRNTGK (SEQ ID NO:3137),EMFIINRNK (SEQ ID NO:3138), EMFIINRNTK (SEQ ID NO:3139), EMFIINRNTGK(SEQ ID NO:3140), ENKDK (SEQ ID NO:3141), ENKDTK (SEQ ID NO:3142),ENKDTGK (SEQ ID NO:3143), ELNKDK (SEQ ID NO:3144), ELNKDTK (SEQ IDNO:3145), ELNKDTGK (SEQ ID NO:3146), EYLNKDK (SEQ ID NO:3147), EYLNKDTK(SEQ ID NO:3148), EYLNKDTGK (SEQ ID NO:3149), EFYLNKDK (SEQ ID NO:3150),EFYLNKDTK (SEQ ID NO:3151), EFYLNKDTGK (SEQ ID NO:3152), EVFYLNKDK (SEQID NO:3153), EVFYLNKDTK (SEQ ID NO:3154), EVFYLNKDTGK (SEQ ID NO:3155),KNQKD (SEQ ID NO:3156), KNQKTD (SEQ ID NO:3157), KNQKTGD (SEQ IDNO:3158), KINQKD (SEQ ID NO:3159), KINQKTD (SEQ ID NO:3160), KINQKTGD(SEQ ID NO:3161), KVINQKD (SEQ ID NO:3162), KVINQKTD (SEQ ID NO:3163),KVINQKTGD (SEQ ID NO:3164), KFVINQKD (SEQ ID NO:3165), KFVINQKTD (SEQ IDNO:3166), KFVINQKTGD (SEQ ID NO:3167), KIFVINQKD (SEQ ID NO:3168),KIFVINQKTD (SEQ ID NO:3169), KIFVINQKTGD (SEQ ID NO:3170), KNRND (SEQ IDNO:3171), KNRNTD (SEQ ID NO:3172), KNRNTGD (SEQ ID NO:3173), KINRND (SEQID NO:3174), KINRNTD (SEQ ID NO:3175), KINRNTGD (SEQ ID NO:3176),KIINRND (SEQ ID NO:3177), KIINRNTD (SEQ ID NO:3178), KIINRNTGD (SEQ IDNO:3179), KFIINRND (SEQ ID NO:3180), KFIINRNTD (SEQ ID NO:3181),KFIINRNTGD (SEQ ID NO:3182), KMFIINRND (SEQ ID NO:3183), KMFIINRNTD (SEQID NO:3184), KMFIINRNTGD (SEQ ID NO:3185), KNKDD (SEQ ID NO:3186),KNKDTD (SEQ ID NO:3187), KNKDTGD (SEQ ID NO:3188), KLNKDD (SEQ IDNO:3189), KLNKDTD (SEQ ID NO:3190) KLNKDTGD (SEQ ID NO:3191), KYLNKDD(SEQ ID NO:3192), KYLNKDTD (SEQ ID NO:3193), KYLNKDTGD (SEQ ID NO:3194),KFYLNKDD (SEQ ID NO:3195), KFYLNKDTD (SEQ ID NO:3196), KFYLNKDTGD (SEQID NO:3197), KVFYLNKDD (SEQ ID NO:3198), KVFYLNKDTD (SEQ ID NO:3199),KVFYLNKDTGD (SEQ ID NO:3200), DNQKK (SEQ ID NO:3201), DNQKTK (SEQ IDNO:3202), DNQKTGK (SEQ ID NO:3203), DINQKK (SEQ ID NO:3204), DINQKTK(SEQ ID NO:3205), DINQKTGK (SEQ ID NO:3206), DVINQKK (SEQ ID NO:3207),DVINQKTK (SEQ ID NO:3208), DVINQKTGK (SEQ ID NO:3209), DFVINQKK (SEQ IDNO:3210), DFVINQKTK (SEQ ID NO:3211), DFVINQKTGK (SEQ ID NO:3212),DIFVINQKK (SEQ ID NO:3213), DIFVINQKTK (SEQ ID NO:3214), DIFVINQKTGK(SEQ ID NO:3215), DNRNK (SEQ ID NO:3216), DNRNTK (SEQ ID NO:3217),DNRNTGK (SEQ ID NO:3218), DINRNK (SEQ ID NO:3219), DINRNTK (SEQ IDNO:3220), DINRNTGK (SEQ ID NO:3221), DIINRNK (SEQ ID NO:3222), DIINRNTK(SEQ ID NO:3223), DIINRNTGK (SEQ ID NO:3224), DFIINRNK (SEQ ID NO:3225),DFIINRNTK (SEQ ID NO:3226), DFIINRNTGK (SEQ ID NO:3227), DMFIINRNK (SEQID NO:3228), DMFIINRNTK (SEQ ID NO:3229), DMFIINRNTGK (SEQ ID NO:3230),DNKDK (SEQ ID NO:3231), DNKDTK (SEQ ID NO:3232), DNKDTGK (SEQ IDNO:3233), DLNKDK (SEQ ID NO:3234), DLNKDTK (SEQ ID NO:3235), DLNKDTGK(SEQ ID NO:3236), DYLNKDK (SEQ ID NO:3237), DYLNKDTK (SEQ ID NO:3238),DYLNKDTGK (SEQ ID NO:3239), DFYLNKDK (SEQ ID NO:3240), DFYLNKDTK (SEQ IDNO:3241), DFYLNKDTGK (SEQ ID NO:3242), DVFYLNKDK (SEQ ID NO:3243),DVFYLNKDTK (SEQ ID NO:3244), DVFYLNKDTGK (SEQ ID NO:3245), KKNQKE (SEQID NO:3246), KNQKTE (SEQ ID NO:3247), KNQKTGE (SEQ ID NO:3248), KINQKE(SEQ ID NO:3249), KINQKTE (SEQ ID NO:3250), KINQKTGE (SEQ ID NO:3251),KVINQKE (SEQ ID NO:3252), KVINQKTE (SEQ ID NO:3253), KVINQKTGE (SEQ IDNO:3254), KFVINQKE (SEQ ID NO:3255), KFVINQKTE (SEQ ID NO:3256),KFVINQKTGE (SEQ ID NO:3257), KIFVINQKE (SEQ ID NO:3258), KIFVINQKTE (SEQID NO:3259), KIFVINQKTGE (SEQ ID NO:3260), KNRNE (SEQ ID NO:3261),KNRNTE (SEQ ID NO:3262), KNRNTGE (SEQ ID NO:3263), KINRNE (SEQ IDNO:3264), KINRNTE (SEQ ID NO:3265), KINRNTGE (SEQ ID NO:3266), KIINRNE(SEQ ID NO:3267), KIINRNTE (SEQ ID NO:3268), KIINRNTGE (SEQ ID NO:3269),KFIINRNE (SEQ ID NO:3270), KFIINRNTE (SEQ ID NO:3271), KFIINRNTGE (SEQID NO:3272), KMFIINRNE (SEQ ID NO:3273), KMFIINRNTE (SEQ ID NO:3274),KMFIINRNTGE (SEQ ID NO:3275), KNKDE (SEQ ID NO:3276), KNKDTE (SEQ IDNO:3277), KNKDTGE (SEQ ID NO:3278), KLNKDE (SEQ ID NO:3279), KLNKDTE(SEQ ID NO:3280), KLNKDTGE (SEQ ID NO:3281), KYLNKDE (SEQ ID NO:3282),KYLNKDTE (SEQ ID NO:3283), KYLNKDTGE (SEQ ID NO:3284), KFYLNKDE (SEQ IDNO:3285), KFYLNKDTE (SEQ ID NO:3286), KFYLNKDTGE (SEQ ID NO:3287),KVFYLNKDE (SEQ ID NO:3288), KVFYLNKDTE (SEQ ID NO:3289), KVFYLNKDTGE(SEQ ID NO:3290), NQKTG (SEQ ID NO:3291), INQKT (SEQ ID NO:3292), INQKTG(SEQ ID NO:3293), VINQK (SEQ ID NO:3294), VINQKT (SEQ ID NO:3295),VINQKTG (SEQ ID NO:3296), FVINQK (SEQ ID NO:3297), FVINQKT (SEQ IDNO:3298), FVINQKTG (SEQ ID NO:3299), IFVINQK (SEQ ID NO:3300), IFVINQKT(SEQ ID NO:3301), IFVINQKTG (SEQ ID NO:3302), NRNTG (SEQ ID NO:3303),INRNT (SEQ ID NO:3304), INRNTG (SEQ ID NO:3305), IINRN (SEQ ID NO:3306),IINRNT (SEQ ID NO:3307), IINRNTG (SEQ ID NO:3308), FIINRN (SEQ IDNO:3309), FIINRNT (SEQ ID NO:3310), FIINRNTG (SEQ ID NO:3311), MFIINRN(SEQ ID NO:3312), MFIINRNT (SEQ ID NO:3313), MFIINRNTG (SEQ ID NO:3314),NKDTG (SEQ ID NO:3315), LNKDT (SEQ ID NO:3316), LNKDTG (SEQ ID NO:3317),YLNKD (SEQ ID NO:3318), YLNKDT (SEQ ID NO:3319), YLNKDTG (SEQ IDNO:3320), FYLNKD (SEQ ID NO:3321), FYLNKDT (SEQ ID NO:3322), FYLNKDTG(SEQ ID NO:3323), VFYLNKD (SEQ ID NO:3324), VFYLNKDT (SEQ ID NO:3325)and VFYLNKDTG (SEQ ID NO:3326).

[0127] Representative cyclic peptides comprising a desmocollin CARsequence include: CEKDC (SEQ ID NO:3327), CEKDTC (SEQ ID NO:3328),CEKDTGC (SEQ ID NO:3329), CIEKDC (SEQ ID NO:3330), CIEKDTC (SEQ IDNO:3331), CIEKDTGC (SEQ ID NO:3332), CYIEKDC (SEQ ID NO:3333), CYIEKDTC(SEQ ID NO:3334), CYIEKDTGC (SEQ ID NO:3335), CFYIEKDC (SEQ ID NO:3336),CFYIEKDTC (SEQ ID NO:3337), CFYIEKDTGC (SEQ ID NO:3338), CLFYIEKDC (SEQID NO:3339), CLFYIEKDTC (SEQ ID NO:3340), CLFYIEKDTGC (SEQ ID NO:3341),CERDC (SEQ ID NO:3342), CERDTC (SEQ ID NO:3343), CERDTGC (SEQ IDNO:3344), CVERDC (SEQ ID NO:3345), CVERDTC (SEQ ID NO:3346), CVERDTGC(SEQ ID NO:3347), CYVERDC (SEQ ID NO:3348), CYVERDTC (SEQ ID NO:3349),CYVERDTGC (SEQ ID NO:3350), CFYVERDC (SEQ ID NO:3351), CFYVERDTC (SEQ IDNO:3352), CFYVERDTGC (SEQ ID NO:3353), CLFYVERDC (SEQ ID NO:3354),CLFYVERDTC (SEQ ID NO:3355), CLFYVERDTGC (SEQ ID NO:3356), CIERDC (SEQID NO:3357), CIERDTC (SEQ ID NO:3358), CIERDTGC (SEQ ID NO:3359),CYIERDC (SEQ ID NO:3360), CYIERDTC (SEQ ID NO:3361), CYIERDTGC (SEQ IDNO:3362), CFYIERDC (SEQ ID NO:3363), CFYIERDTC (SEQ ID NO:3364),CFYIERDTGC (SEQ ID NO:3365), CLFYIERDC (SEQ ID NO:3366), CLFYIERDTC (SEQID NO:3367), CLFYIERDTGC (SEQ ID NO:3368), EEKDK (SEQ ID NO:3369),EEKDTK (SEQ ID NO:3370), EEKDTGK (SEQ ID NO:3371), EIEKDK (SEQ IDNO:3372), EIEKDTK (SEQ ID NO:3373), EIEKDTGK (SEQ ID NO:3374), EYIEKDK(SEQ ID NO:3375), EYIEKDTK (SEQ ID NO:3376), EYIEKDTGK (SEQ ID NO:3377),EFYIEKDK (SEQ ID NO:3378), EFYIEKDTK (SEQ ID NO:3379), EFYIEKDTGK (SEQID NO:3380), ELFYIEKDK (SEQ ID NO:3381), ELFYIEKDTK (SEQ ID NO:3382),ELFYIEKDTGK (SEQ ID NO:3383), EERDK (SEQ ID NO:3384), EERDTK (SEQ IDNO:3385), EERDTGK (SEQ ID NO:3386), EVERDK (SEQ ID NO:3387), EVERDTK(SEQ ID NO:3388), EVERDTGK (SEQ ID NO:3389), EYVERDK (SEQ ID NO:3390),YVERDTK (SEQ ID NO:3391), EYVERDTGK (SEQ ID NO:3392), EFYVERDK (SEQ IDNO:3393), EFYVERDTK (SEQ ID NO:3394), EFYVERDTGK (SEQ ID NO:3395),ELFYVERDK (SEQ ID NO:3396), ELFYVERDTK (SEQ ID NO:3397), ELFYVERDTGK(SEQ ID NO:3398), EIERDK (SEQ ID NO:3399), EIERDTK (SEQ ID NO:3400),EIERDTGK (SEQ ID NO:3401), EYIERDK (SEQ ID NO:3402), EYIERDTK (SEQ IDNO:3403), EYIERDTGK (SEQ ID NO:3404), EFYIERDK (SEQ ID NO:3405),EFYIERDTK (SEQ ID NO:3406), EFYIERDTGK (SEQ ID NO:3407), ELFYIERDK (SEQID NO:3408), ELFYIERDTK (SEQ ID NO:3409), ELFYIERDTGK (SEQ ID NO:3410),KEKDD (SEQ ID NO:3411), KEKDTD (SEQ ID NO:3412), KEKDTGD (SEQ IDNO:3413), KIEKDD (SEQ ID NO:3414), KIEKDTD (SEQ ID NO:3415), KIEKDTGD(SEQ ID NO:3416), KYIEKDD (SEQ ID NO:3417), KYIEKDTD (SEQ ID NO:3418),KYIEKDTGD (SEQ ID NO:3419), KFYIEKDD (SEQ ID NO:3420), KFYIEKDTD (SEQ IDNO:-3421), KFYIEKDTGD (SEQ ID NO:3422), KLFYIEKDD (SEQ ID NO:3423),KLFYIEKDTD (SEQ ID NO:3424), KLFYIEKDTGD (SEQ ID NO:3425), KERDD (SEQ IDNO:3426), KERDTD (SEQ ID NO:3427), KERDTGD (SEQ ID NO:3428), KVERDD (SEQID NO:3429), KVERDTD (SEQ ID NO:3430), KVERDTGD (SEQ ID NO:3431),KYVERDD (SEQ ID NO:3432), KYVERDTD (SEQ ID NO:3433), KYVERDTGD (SEQ IDNO:3434), KFYVERDD (SEQ ID NO:3435), KFYVERDTD (SEQ ID NO:3436),KFYVERDTGD (SEQ ID NO:3437), KLFYVERDD (SEQ ID NO:3438), KLFYVERDTD (SEQID NO:3439), KLFYVERDTGD (SEQ ID NO:3440), KIERDD (SEQ ID NO:3441),KIERDTD (SEQ ID NO:3442), KIERDTGD (SEQ ID NO:3443), KYIERD (SEQ IDNO:3444), KYIERDTD (SEQ ID NO:3445), KYIERDTGD (SEQ ID NO:3446),KFYIERDD (SEQ ID NO:3447), KFYIERDTD (SEQ ID NO:3448), KFYIERDTGD (SEQID NO:3449), KLFYIERDD (SEQ ID NO:3450), KLFYIERDTD (SEQ ID NO:3451),KLFYIERDTGD (SEQ ID NO:3452), DEKDK (SEQ ID NO:3453), DEKDTK (SEQ IDNO:3454), DEKDTGK (SEQ ID NO:3455), DIEKDK (SEQ ID NO:3456), DIEKDTK(SEQ ID NO:3457), DIEKDTGK (SEQ ID NO:3458), DYIEKDK (SEQ ID NO:3459),DYIEKDTK (SEQ ID NO:3460), DYIEKDTGK (SEQ ID NO:3461), DFYIEKDK (SEQ IDNO:3462), DFYIEKDTK (SEQ ID NO:3463), DFYIEKDTGK (SEQ ID NO:3464),DLFYIEKDK (SEQ ID NO:3465), DLFYIEKDTK (SEQ ID NO:3466), DLFYIEKDTGK(SEQ ID NO:3467), DERDK (SEQ ID NO:3468), DERDTK (SEQ ID NO:3469),DERDTGK (SEQ ID NO:3470), DVERDK (SEQ ID NO:3471), DVERDTK (SEQ IDNO:3472), DVERDTGK (SEQ ID NO:3473), DYVERDK (SEQ ID NO:3474), DYVERDTK(SEQ ID NO:3475), DYVERDTGK (SEQ ID NO:3476), DFYVERDK (SEQ ID NO:3477),DFYVERDTK (SEQ ID NO:3478), DFYVERDTGK (SEQ ID NO:3479), DLFYVERDK (SEQID NO:3480), DLFYVERDTK (SEQ ID NO:3481), DLFYVERDTGK (SEQ ID NO:3482),DIERDK (SEQ ID NO:3483), DIERDTK (SEQ ID NO:3484), DIERDTGK (SEQ IDNO:3485), DYIERDK (SEQ ID NO:3486), DYIERDTK (SEQ ID NO:3487), DYIERDTGK(SEQ ID NO:3488), DFYIERDK (SEQ ID NO:3489), DFYIERDTK (SEQ ID NO:3490),DFYIERDTGK (SEQ ID NO:3491), DLFYIERDK (SEQ ID NO:3492), DLFYIERDTK (SEQID NO:3493), DLFYIERDTGK (SEQ ID NO:3494), KEKDE (SEQ ID NO:3495),KEKDTE (SEQ ID NO:3496), KEKDTGE (SEQ ID NO:3497), KIEKDE (SEQ IDNO:3498), KIEKDTE (SEQ ID NO:3499), KIEKDTGE (SEQ ID NO:3500), KYIEKDE(SEQ ID NO:3501), KYIEKDTE (SEQ ID NO:3502), KYIEKDTGE (SEQ ID NO:3503),KFYIEKDE (SEQ ID NO:3504), KFYIEKDTE (SEQ ID NO:3505), KFYIEKDTGE (SEQID NO:3506), KLFYIEKDE (SEQ ID NO:3507), KLFYIEKDTE (SEQ ID NO:3508),KLFYIEKDTGE (SEQ ID NO:3509), KERDE (SEQ ID NO:3510), KERDTE (SEQ IDNO:3511), KERDTGE (SEQ ID NO:3512), KVERDE (SEQ ID NO:3513), KVERDTE(SEQ ID NO:3514), KVERDTGE (SEQ ID NO:3515), KYVERDE (SEQ ID NO:3516),KYVERDTE (SEQ ID NO:3517), KYVERDTGE (SEQ ID NO:3518), KFYVERDE (SEQ IDNO:3519), KFYVERDTE (SEQ ID NO:3520), KFYVERDTGE (SEQ ID NO:3521),KLFYVERDE (SEQ ID NO:3522), KLFYVERDTE (SEQ ID NO:3523), KLFYVERDTGE(SEQ ID NO:3524), KIERDE (SEQ ID NO:3525), KIERDTE (SEQ ID NO:3526),KIERDTGE (SEQ ID NO:3527), KYIERDE (SEQ ID NO:3528), KYIERDTE (SEQ IDNO:3529), KYIERDTGE (SEQ ID NO:3530), KFYIERDE (SEQ ID NO:3531),KFYIERDTE (SEQ ID NO:3532), KFYIERDTGE (SEQ ID NO:3533), KLFYIERDE (SEQID NO:3534), KLFYIERDTE (SEQ ID NO:3535), KLFYIERDTGE (SEQ ID NO:3536),EKDTG (SEQ ID NO:3537), IEKDT (SEQ ID NO:3538), IEKDTG (SEQ ID NO:3539),YIEKD (SEQ ID NO:3540), YIEKDT (SEQ ID NO:3541), YIEKDTG (SEQ IDNO:3542), FYIEKD (SEQ ID NO:3543), FYIEKDT (SEQ ID NO:3544), FYIEKDTG(SEQ ID NO:3545), LFYIEKD (SEQ ID NO:3546), LFYIEKDT (SEQ ID NO:3547),LFYIEKDTG (SEQ ID NO:3548), ERDTG (SEQ ID NO:3549), VERDT (SEQ IDNO:3550), VERDTG (SEQ ID NO:3551), YVERD (SEQ ID NO:3552), YVERDT (SEQID NO:3553), YVERDTG (SEQ ID NO:3554), FYVERD (SEQ ID NO:3555), FYVERDT(SEQ ID NO:3556), FYVERDTG (SEQ ID NO:3557), LFYVERD (SEQ ID NO:3558),LFYVERDT (SEQ ID NO:3559), LFYVERDTG (SEQ ID NO:3560), IERDT (SEQ IDNO:3561), IERDTG (SEQ ID NO:3562), YIERD (SEQ ID NO:3563), YIERDT (SEQID NO:3564), YIERDTG (SEQ ID NO:3565), FYIERD (SEQ ID NO:3566), FYIERDT(SEQ ID NO:3567), FYIERDTG (SEQ ID NO:3568), LFYIERD (SEQ ID NO:3569),LFYIERDT (SEQ ID NO:3570) and LFYIERDTG (SEQ ID NO:3571).

[0128] Representative cyclic peptides comprising a cnr CAR sequenceinclude: CDPVC (SEQ ID NO:3572), CDPVSC (SEQ ID NO:3573), CDPVSGC (SEQID NO:3574), CIDPVC (SEQ ID NO:3575), CIDPVSC (SEQ ID NO:3576), CIDPVSGC(SEQ ID NO:3577), CHIDPVC (SEQ ID NO:3578), CHIDPVSC (SEQ ID NO:3579),CHIDPVSGC (SEQ ID NO:3580), CFHIDPVC (SEQ ID NO:3581), CFHIDPVSC (SEQ IDNO:3582), CFHIDPVSGC (SEQ ID NO:3583), CKFHIDPVC (SEQ ID NO:3584),CKFHIDPVSC (SEQ ID NO:3585), CKFHIDPVSGC (SEQ ID NO:3586), CDADC (SEQ IDNO:3587), CDADTC (SEQ ID NO:3588), CDADTGC (SEQ ID NO:3589), CIDADTC(SEQ ID NO:3590), CIDADC (SEQ ID NO:3591), CIDADTGC (SEQ ID NO:3592),CSIDADC (SEQ ID NO:3593), CSIDADTC (SEQ ID NO:3594), CSIDADTGC (SEQ IDNO:3595), CFSIDADC (SEQ ID NO:3596), CFSIDADTC (SEQ ID NO:3597),CFSIDADTGC (SEQ ID NO:3598), CQFSIDADC (SEQ ID NO:3599), CQFSIDADTC (SEQID NO:3600), CQFSIDADTGC (SEQ ID NO:3601), CDSVC (SEQ ID NO:3602),CDSVSC (SEQ ID NO:3603), CDSVSGC (SEQ ID NO:3604), CIDSVC (SEQ IDNO:3605), CIDSVSC (SEQ ID NO:3606), CIDSVSGC (SEQ ID NO:3607), CHIDSVC(SEQ ID NO:3608), CHIDSVSC (SEQ ID NO:3609), CHIDSVSGC (SEQ ID NO:3610),CFHIDSVC (SEQ ID NO:3611), CFHIDSVSC (SEQ ID NO:3612), CFHIDSVSGC (SEQID NO:3613), CTFHIDSVC (SEQ ID NO:3614), CTFHIDSVSC (SEQ ID NO:3615),CTFHIDSVSGC (SEQ ID NO:3616), CDSNC (SEQ ID NO:3617), CDSNSC (SEQ IDNO:3618), CDSNSGC (SEQ ID NO:3619), CIDSNC (SEQ ID NO:3620), CIDSNSC(SEQ ID NO:3621), CIDSNSGC (SEQ ID NO:3622), CNIDSNC (SEQ ID NO:3623),CNIDSNSC (SEQ ID NO:3624), CNIDSNSGC (SEQ ID NO:3625), CFNIDSNC (SEQ IDNO:3626), CFNIDSNSC (SEQ ID NO:3627), CFNIDSNSGC (SEQ ID NO:3628),CAFNIDSNC (SEQ ID NO:3629), CAFNIDSNSC (SEQ ID NO:3631), CAFNIDSNSGC(SEQ ID NO:3632), CDSSC (SEQ ID NO:3633), CDSSSC (SEQ ID NO:3634),CDSSSGC (SEQ ID NO:3635), CIDSSC (SEQ ID NO:3636), CIDSSSC (SEQ IDNO:3637), CIDSSSGC (SEQ ID NO:3638), CTIDSSC (SEQ ID NO:3639), CTIDSSSC(SEQ ID NO:3640), CTIDSSSGC (SEQ ID NO:3641), CFTIDSSC (SEQ ID NO:3642),CFTIDSSSC (SEQ ID NO:3643), CFTIDSSSGC (SEQ ID NO:3644), CKFTIDSSC (SEQID NO:3645), CKFTIDSSSC (SEQ ID NO:3646), CKFTIDSSSGC (SEQ ID NO:3647),CDEKC (SEQ ID NO:3648), CDEKNC (SEQ ID NO:3649), CDEKNGC (SEQ IDNO:3650), CLDEKC (SEQ ID NO:3651), CLDEKNC (SEQ ID NO:3652), CLDEKNGC(SEQ ID NO:3653), CTLDEKC (SEQ ID NO:3654), CTLDEKNC (SEQ ID NO:3655),CTLDEKNGC (SEQ ID NO:3656), CFTLDEKC (SEQ ID NO:3657), CFTLDEKNC (SEQ IDNO:3658), CFTLDEKNGC (SEQ ID NO:3659), CLFTLDEKC (SEQ ID NO:3660),CLFTLDEKNC (SEQ ID NO:3661), CLFTLDEKNGC (SEQ ID NO:3662), CNEKC (SEQ IDNO:3663), CNEKTC (SEQ ID NO:3664), CNEKTGC (SEQ ID NO:3665), CINEKC (SEQID NO:3666), CINEKTC (SEQ ID NO:3667), CINEKTGC (SEQ ID NO:3668),CLINEKC (SEQ ID NO:3669), CLINEKTC (SEQ ID NO:3670), CLINEKTGC (SEQ IDNO:3671), CFLINEKC (SEQ ID NO:3672), CFLINEKTC (SEQ ID NO:3673),CFLINEKTGC (SEQ ID NO:3674), CKFLINEKC (SEQ ID NO:3675), CKFLINEKTC (SEQID NO:3676), CKFLINEKTGC (SEQ ID NO:3677), EDPVK (SEQ ID NO:3678),EDPVSK (SEQ ID NO:3679), EDPVSGK (SEQ ID NO:3680), EIDPVK (SEQ IDNO:3681), EIDPVSK (SEQ ID NO:3682), EIDPVSGK (SEQ ID NO:3683), EHIDPVK(SEQ ID NO:3684), EHIDPVSK (SEQ ID NO:3685), EHIDPVSGK (SEQ ID NO:3686),EFHIDPVK (SEQ ID NO:3687), EFHIDPVSK (SEQ ID NO:3688), EFHIDPVSGK (SEQID NO:3689), EKFHIDPVK (SEQ ID NO:3690), EKFHIDPVSK (SEQ ID NO:3691),EKFHIDPVSGK (SEQ ID NO:3692), EDADK (SEQ ID NO:3693), EDADTK (SEQ IDNO:3694), EDADTGK (SEQ ID NO:3695), EIDADK (SEQ ID NO:3696), EIDADTK(SEQ ID NO:3697), EIDADTGK (SEQ ID NO:3698), ESIDADK (SEQ ID NO:3699),ESIDADTK (SEQ ID NO:3700), ESIDADTGK (SEQ ID NO:3701), EFSIDADK (SEQ IDNO:3702), EFSIDADTK (SEQ ID NO:3703), EFSIDADTGK (SEQ ID NO:3704),EQFSIDADK (SEQ ID NO:3705), EQFSIDADTK (SEQ ID NO:3706), EQFSIDADTGK(SEQ ID NO:3707), EDSVK (SEQ ID NO:3708), EDSVSK (SEQ ID NO:3709),EDSVSGK (SEQ ID NO:3710), EIDSVK (SEQ ID NO:3711), EIDSVSK (SEQ IDNO:3712), EIDSVSGK (SEQ ID NO:3713), EHIDSVK (SEQ ID NO:3714), EHIDSVSK(SEQ ID NO:3715), EHIDSVSGK (SEQ ID NO:3716), EFHIDSVK (SEQ ID NO:3717),EFHIDSVSK (SEQ ID NO:3718), EFHIDSVSGK (SEQ ID NO:3719), ETFHIDSVK (SEQID NO:3720), ETFHIDSVSK (SEQ ID NO:3721), ETFHIDSVSGK (SEQ ID NO:3722),EDSNK (SEQ ID NO:3723), EDSNSK (SEQ ID NO:3724), EDSNSGK (SEQ IDNO:3725), EIDSNK (SEQ ID NO:3726), EIDSNSK (SEQ ID NO:3727), EIDSNSGK(SEQ ID NO:3728), ENIDSNK (SEQ ID NO:3729), ENIDSNSK (SEQ ID NO:3730),ENIDSNSGK (SEQ ID NO:3731), EFNIDSNK (SEQ ID NO:3732), EFNIDSNSK (SEQ IDNO:3733), EFNIDSNSGK (SEQ ID NO:3734), EAFNIDSNK (SEQ ID NO:3735),EAFNIDSNSK (SEQ ID NO:3737), EAFNIDSNSGK (SEQ ID NO:3738), EDSSK (SEQ IDNO:3739), EDSSSK (SEQ ID NO:3740), EDSSSGK (SEQ ID NO:3741), EIDSSK (SEQID NO:3742), EIDSSSK (SEQ ID NO:3743), EIDSSSGK (SEQ ID NO:3744),ETIDSSK (SEQ ID NO:3745), ETIDSSSK (SEQ ID NO:3746), ETIDSSSGK (SEQ IDNO:3747), EFTIDSSK (SEQ ID NO:3748), EFTIDSSSK (SEQ ID NO:3749),EFTIDSSSGK (SEQ ID NO:3750), EKFTIDSSK (SEQ ID NO:3751), EKFTIDSSSK (SEQID NO:3752), EKFTIDSSSGK (SEQ ID NO:3753), EDEKK (SEQ ID NO:3754),EDEKNK (SEQ ID NO:3755), EDEKNGK (SEQ ID NO:3756), ELDEKK (SEQ IDNO:3757), ELDEKNK (SEQ ID NO:3758), ELDEKNGK (SEQ ID NO:3759), ETLDEKK(SEQ ID NO:3760), ETLDEKNK (SEQ ID NO:3761), ETLDEKNGK (SEQ ID NO:3762),EFTLDEKK (SEQ ID NO:3763), EFTLDEKNK (SEQ ID NO:3764), EFTLDEKNGK (SEQID NO:3765), ELFTLDEKK (SEQ ID NO:3766), ELFTLDEKNK (SEQ ID NO:3767),ELFTLDEKNGK (SEQ ID NO:3768), ENEKK (SEQ ID NO:3769), ENEKTK (SEQ IDNO:3770), ENEKTGK (SEQ ID NO:3771), EINEKK (SEQ ID NO:3772), EINEKTK(SEQ ID NO:3773), EINEKTGK (SEQ ID NO:3774), ELINEKK (SEQ ID NO:3775),ELINEKTK (SEQ ID NO:3776), ELINEKTGK (SEQ ID NO:3777), EFLINEKK (SEQ IDNO:3778), EFLINEKTK (SEQ ID NO:3779), EFLINEKTGK (SEQ ID NO:3780),EKFLINEKK (SEQ ID NO:3781), EKFLINEKTK (SEQ ID NO:3782), EKFLINEKTGK(SEQ ID NO:3783), KDPVD (SEQ ID NO:3784), KDPVSD (SEQ ID NO:3785),KDPVSGD (SEQ ID NO:3786), KIDPVD (SEQ ID NO:3787), KIDPVSD (SEQ IDNO:3788), KIDPVSGD (SEQ ID NO:3789), KHIDPVD (SEQ ID NO:3790), KHIDPVSD(SEQ ID NO:3791), KHIDPVSGD (SEQ ID NO:3792), KFHIDPVD (SEQ ID NO:3793),KFHIDPVSD (SEQ ID NO:3794), KFHIDPVSGD (SEQ ID NO:3795), KKFHIDPVD (SEQID NO:3796), KKFHIDPVSD (SEQ ID NO:3797), KKFHIDPVSGD (SEQ ID NO:3798),KDADD (SEQ ID NO:3799), KDADTD (SEQ ID NO:3800), KDADTGD (SEQ IDNO:3801), KIDADD (SEQ ID NO:3802), KIDADTD (SEQ ID NO:3803), KIDADTGD(SEQ ID NO:3804), KSIDADD (SEQ ID NO:3805), KSIDADTD (SEQ ID NO:3806),KSIDADTGD (SEQ ID NO:3807), KFSIDADD (SEQ ID NO:3808), KFSIDADTD (SEQ IDNO:3809), KFSIDADTGD (SEQ ID NO:3810), KQFSIDADD (SEQ ID NO:3811),KQFSIDADTD (SEQ ID NO:3812), KQFSIDADTGD (SEQ ID NO:3813), KDSVD (SEQ IDNO:3814), KDSVSD (SEQ ID NO:3815), KDSVSGD (SEQ ID NO:3816), KIDSVD (SEQID NO:3817), KIDSVSD (SEQ ID NO:3818), KIDSVSGD (SEQ ID NO:3819),KHIDSVD (SEQ ID NO:3820), KHIDSVSD (SEQ ID NO:3821), KHIDSVSGD (SEQ IDNO:3822), KFHIDSVD (SEQ ID NO:3823), KFHIDSVSD (SEQ ID NO:3824),KFHIDSVSGD (SEQ ID NO:3825), KTFHIDSVD (SEQ ID NO:3826), KTFHIDSVSD (SEQID NO:3827), KTFHIDSVSGD (SEQ ID NO:3828), KDSND (SEQ ID NO:3829),KDSNSD (SEQ ID NO:3830), KDSNSGD (SEQ ID NO:3831), KIDSND (SEQ IDNO:3832), KIDSNSD (SEQ ID NO:3833), KIDSNSGD (SEQ ID NO:3834), KNIDSND(SEQ ID NO:3835), KNIDSNSD (SEQ ID NO:3836), KNIDSNSGD (SEQ ID NO:3837),KFNIDSND (SEQ ID NO:3838), KFNIDSNSD (SEQ ID NO:3839), KFNIDSNSGD (SEQID NO:3840), KAFNIDSND (SEQ ID NO:3841), KAFNIDSNSD (SEQ ID NO:3843),KAFNIDSNSGD (SEQ ID NO:3844), KDSSD (SEQ ID NO:3845), KDSSSD (SEQ IDNO:3846), KDSSSGD (SEQ ID NO:3847), KIDSSD (SEQ ID NO:3848), KIDSSSD(SEQ ID NO:3849), KIDSSSGD (SEQ ID NO:3850), KTIDSSD (SEQ ID NO:3851),KTIDSSSD (SEQ ID NO:3852), KTIDSSSGD (SEQ ID NO:3853), KFTIDSSD (SEQ IDNO:3854), KFTIDSSSD (SEQ ID NO:3855), KFTIDSSSGD (SEQ ID NO:3856),KKFTIDSSD (SEQ ID NO:3857), KKFTIDSSSD (SEQ ID NO:3858), KKFTIDSSSGD(SEQ ID NO:3859), KDEKD (SEQ ID NO:3860), KDEKND (SEQ ID NO:3861),KDEKNGD (SEQ ID NO:3862), KLDEKD (SEQ ID NO:3863), KLDEKND (SEQ IDNO:3864), KLDEKNGD (SEQ ID NO:3865), KTLDEKD (SEQ ID NO:3866), KTLDEKND(SEQ ID NO:3867), KTLDEKNGD (SEQ ID NO:3868), KFTLDEKD (SEQ ID NO:3869),KFTLDEKND (SEQ ID NO:3870), KFTLDEKNGD (SEQ ID NO:3871), KLFTLDEKD (SEQID NO:3872), KLFTLDEKND (SEQ ID NO:3873), KLFTLDEKNGD (SEQ ID NO:3874),KNEKD (SEQ ID NO:3875), KNEKTD (SEQ ID NO:3876), KNEKTGD (SEQ IDNO:3877), KINEKD (SEQ ID NO:3878), KINEKTD (SEQ ID NO:3879), KINEKTGD(SEQ ID NO:3880), KLINEKD (SEQ ID NO:3881), KLINEKTD (SEQ ID NO:3882),KLINEKTGD (SEQ ID NO:3883), KFLINEKD (SEQ ID NO:3884), KFLINEKTD (SEQ IDNO:3885), KFLINEKTGD (SEQ ID NO:3886), KKFLINEKD (SEQ ID NO:3887),KKFLINEKTD (SEQ ID NO:3888) and KKFLINEKTGD (SEQ ID NO:3889).

[0129] As noted above, certain preferred modulating agents comprise apeptide (containing a nonclassical cadherin CAR sequence or an analoguethereof) in which at least one terminal amino acid residue is modified(e.g., the N-terminal amino group is modified by, for example,acetylation or alkoxybenzylation and/or an amide or ester is formed atthe C-terminus). It has been found, within the context of the presentinvention, that the addition of at least one such group to a linear orcyclic peptide modulating agent may improve the ability of the agent tomodulate a nonclassical cadherin-mediated function. Certain preferredmodulating agents contain modifications at the N- and C-terminalresidues, such as N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85), which modulatesOB-cadherin mediated functions. Other CAR sequences provided herein arealso preferably modified by the addition of one or more terminal groups.

[0130] The present invention further contemplates nonclassical cadherinCAR sequences from other organisms. Such CAR sequences may be identifiedbased upon sequence similarity to the sequences provided herein, and theability to modulate a nonclassical cadherin-mediated function such asmay be confirmed as described herein.

[0131] Within certain embodiments, as discussed below, cyclic peptidesthat contain small CAR sequences (e.g., three residues withoutsignificant flanking sequences) are preferred for modulatingnonclassical cadherin-mediated functions. Such peptides may contain anN-acetyl group and a C-amide group (e.g., the 5-residue ringN-Ac-CDDKC-NH₂ (SEQ ID NO:669) or N-Ac-KDDKD-NH₂ (SEQ ID NO:697), formodulating OB-cadherin mediated functions). Small cyclic peptides maygenerally be used to specifically modulate adhesion of cancer and/orother cell types by topical administration or by systemicadministration, with or without linking a targeting agent to thepeptide, as discussed below. Certain representative cyclic peptidescomprising an OB-cadherin CAR sequence are shown in FIGS. 4A-4C. Otherrepresentative cyclic peptides comprising a nonclassical cadherin CARsequence are shown in FIGS. 7A-7F.

[0132] Within embodiments in which inhibition of a nonclassicalcadherin-interaction is desired, a modulating agent may contain onenonclassical cadherin CAR sequence, or multiple CAR sequences that areadjacent to one another (i.e., without intervening sequences) or inclose proximity (i.e., separated by peptide and/or non-peptide linkersto give a distance between the nonclassical CAR sequences that rangesfrom about 0.1 to 400 nm). A linker may be any molecule (includingpeptide and/or non-peptide sequences) that does not contain a CARsequence and that can be covalently linked to at least two peptidesequences. Using a linker, CAR sequence-containing peptides and otherpeptide or protein sequences may be joined end-to-end (i.e., the linkermay be covalently attached to the carboxyl or amino group of eachpeptide sequence), and/or via side chains. One linker that can be usedfor such purposes is (H₂N(CH₂)_(n)CO₂H), or derivatives thereof, where nranges from 1 to 4. Other linkers that may be used will be apparent tothose of ordinary skill in the art. Peptide and non-peptide linkers maygenerally be incorporated into a modulating agent using any appropriatemethod known in the art.

[0133] Within embodiments in which enhancement of cell adhesion mediatedby a nonclassical cadherin is desired, a modulating agent may containmultiple nonclassical cadherin CAR sequences, or antibodies thatspecifically bind to such sequences, joined by linkers as describedabove. For enhancers of cadherin function, the linker distance shouldgenerally be 400-10,000 nm. One linker that can be used for suchpurposes is (H₂N(CH₂)_(n)CO2H)_(m), or derivatives thereof, where nranges from 1 to 10 and m ranges from 1 to 4000. For example, if glycine(H₂NCH₂CO₂H) or a multimer thereof is used as a linker, each glycineunit corresponds to a linking distance of 2.45 angstroms, or 0.245 nm,as determined by calculation of its lowest energy conformation whenlinked to other amino acids using molecular modeling techniques.Similarly, aminopropanoic acid corresponds to a linking distance of 3.73angstroms, aminobutanoic acid to 4.96 angstroms, aminopentanoic acid to6.30 angstroms and amino hexanoic acid to 6.12 angstroms. Enhancement ofcell adhesion may also be achieved by attachment of multiple modulatingagents to a support material, as discussed further below.

[0134] A modulating agent as described herein may additionally compriseone or more CAR sequences for one or more different adhesion molecules(including, but not limited to, other CAMs) and/or one or moresubstances, such as antibodies or fragments thereof, that bind to suchsequences. Linkers may, but need not, be used to separate such CARsequence(s) and/or antibody sequence(s) from the CAR sequence(s) and/oreach other. Such modulating agents may generally be used within methodsin which it is desirable to simultaneously disrupt a function mediatedby multiple adhesion molecules. As used herein, an “adhesion molecule”is any molecule that mediates cell adhesion via a receptor on a cell'ssurface. Adhesion molecules include cell adhesion proteins (e.g., othermembers of the cadherin gene superfamily, such as N-cadherin andE-cadherin); integrins; extracellular matrix proteins such as laminin,fibronectin, collagens, vitronectin, entactin and tenascin; and membersof the immunoglobulin supergene family, such as N-CAM. Preferred CARsequences for inclusion within a modulating agent include the classicalcadherin CAR sequence His-Ala-Val (HAV); Arg-Gly-Asp (RGD), which isbound by integrins (see Cardarelli et al., J. Biol. Chem. 267:23159-64,1992); Tyr-lle-Gly-Ser-Arg (YIGSR; SEQ ID NO:48), which is bound by α6μ1integrin; KYSFNYDGSE (SEQ ID NO:49), which is bound by N-CAM; the N-CAMheparin sulfate-binding site IWKHKGRDVILKKDVRF (SEQ ID NO:50); theputative claudin CAR sequence IYSY (SEQ ID NO:51) and/or the occludinCAR sequence LYHY (SEQ ID NO:52). Using linkers, such modulating agentsmay form linear or branched structures. Within one embodiment,modulating agents having a branched structure comprise four differentCAR sequences, such as IFVIDDKSG (SEQ ID NO:85), RGD, YIGSR (SEQ IDNO:48) and HAV. Bi-functional modulating agents that comprise anonclassical cadherin CAR sequence joined via a linker to a classicalcadherin CAR sequence are also preferred for certain embodiments. Asnoted above, linkers preferably produce a distance between CAR sequencesranging from 0.1 to 10,000 nm, more preferably ranging from 0.1-400 nm.A separation distance between recognition sites may generally bedetermined according to the desired function of the modulating agent.

[0135] The total number of CAR sequences (including the nonclassicalcadherin CAR sequence, with or without other CAR sequences derived fromone or more different adhesion molecules) present within a modulatingagent may range from 1 to a large number, such as 100, preferably from 1to 10, and more preferably from 1 to 5. Peptide modulating agentscomprising multiple CAR sequences typically contain from 6 (e.g.,DDK-HAV) to about 1000 amino acid residues, preferably from 6 to 50residues. When non-peptide linkers are employed, each CAR sequence ofthe modulating agent is present within a peptide that generally rangesin size from 3 to 50 residues in length, preferably from 4 to 25residues, and more preferably from 5 to 15 residues.

[0136] As noted above, modulating agents may be polypeptides or saltsthereof, containing only amino acid residues linked by peptide bonds, ormay contain non-peptide regions, such as linkers. Peptide regions of amodulating agent may comprise residues of L-amino acids, D-amino acids,or any combination thereof. Amino acids may be from natural ornon-natural sources, provided that at least one amino group and at leastone carboxyl group are present in the molecule; α- and β-amino acids aregenerally preferred. The 20 L-amino acids commonly found in proteins areidentified herein by the conventional three-letter or one-letterabbreviations, and the corresponding D-amino acids are designated by alower case one letter symbol.

[0137] A modulating agent may also contain rare amino acids (such as4-hydroxyproline or hydroxylysine), organic acids or amides and/orderivatives of common amino acids, such as amino acids having theC-terminal carboxylate esterified (e.g., benzyl, methyl or ethyl ester)or amidated and/or having modifications of the N-terminal amino group(e.g., acetylation or alkoxycarbonylation), with or without any of awide variety of side-chain modifications and/or substitutions (e.g.,methylation, benzylation, t-butylation, tosylation, alkoxycarbonylation,and the like). Preferred derivatives include amino acids having aC-terminal amide group. Residues other than common amino acids that maybe present with a modulating agent include, but are not limited to,2-mercaptoaniline, 2-mercaptoproline, ornithine, diaminobutyric acid,α-aminoadipic acid, m-aminomethylbenzoic acid and α,β-diaminopropionicacid.

[0138] Peptide modulating agents (and peptide portions of modulatingagents) as described herein may be synthesized by methods well known inthe art, including chemical synthesis and recombinant DNA methods. Formodulating agents up to about 50 residues in length, chemical synthesismay be performed using solution or solid phase peptide synthesistechniques, in which a peptide linkage occurs through the directcondensation of the α-amino group of one amino acid with the α-carboxygroup of the other amino acid with the elimination of a water molecule.Peptide bond synthesis by direct condensation, as formulated above,requires suppression of the reactive character of the amino group of thefirst and of the carboxyl group of the second amino acid. The maskingsubstituents must permit their ready removal, without inducing breakdownof the labile peptide molecule.

[0139] In solution phase synthesis, a wide variety of coupling methodsand protecting groups may be used (see Gross and Meienhofer, eds., “ThePeptides: Analysis, Synthesis, Biology,” Vol. 1-4 (Academic Press,1979); Bodansky and Bodansky, “The Practice of Peptide Synthesis,” 2ded. (Springer Verlag, 1994)). In addition, intermediate purification andlinear scale up are possible. Those of ordinary skill in the art willappreciate that solution synthesis requires consideration of main chainand side chain protecting groups and activation method. In addition,careful segment selection is necessary to minimize racemization duringsegment condensation. Solubility considerations are also a factor.

[0140] Solid phase peptide synthesis uses an insoluble polymer forsupport during organic synthesis The polymer-supported peptide chainpermits the use of simple washing and filtration steps instead oflaborious purifications at intermediate steps. Solid-phase peptidesynthesis may generally be performed according to the method ofMerrifield et al., J. Am. Chem. Soc. 85:2149, 1963, which involvesassembling a linear peptide chain on a resin support using protectedamino acids. Solid phase peptide synthesis typically utilizes either theBoc or Fmoc strategy. The Boc strategy uses a 1% cross-linkedpolystyrene resin. The standard protecting group for α-amino functionsis the tert-butyloxycarbonyl (Boc) group. This group can be removed withdilute solutions of strong acids such as 25% trifluoroacetic acid (TFA).The next Boc-amino acid is typically coupled to the amino acyl resinusing dicyclohexylcarbodiimide (DCC). Following completion of theassembly, the peptide-resin is treated with anhydrous HF to cleave thebenzyl ester link and liberate the free peptide. Side-chain functionalgroups are usually blocked during synthesis by benzyl-derived blockinggroups, which are also cleaved by HF. The free peptide is then extractedfrom the resin with a suitable solvent, purified and characterized.Newly synthesized peptides can be purified, for example, by gelfiltration, HPLC, partition chromatography and/or ion-exchangechromatography, and may be characterized by, for example, massspectrometry or amino acid sequence analysis. In the Boc strategy,C-terminal amidated peptides can be obtained using benzhydrylamine ormethylbenzhydrylamine resins, which yield peptide amides directly uponcleavage with HF.

[0141] In the procedures discussed above, the selectivity of theside-chain blocking groups and of the peptide-resin link depends uponthe differences in the rate of acidolytic cleavage. Orthoganol systemshave been introduced in which the side-chain blocking groups and thepeptide-resin link are completely stable to the reagent used to removethe a-protecting group at each step of the synthesis. The most common ofthese methods involves the 9-fluorenylmethyloxycarbonyl (Fmoc) approach.Within this method, the side-chain protecting groups and thepeptide-resin link are completely stable to the secondary amines usedfor cleaving the N-α-Fmoc group. The side-chain protection and thepeptide-resin link are cleaved by mild acidolysis. The repeated contactwith base makes the Merrifield resin unsuitable for Fmoc chemistry, andp-alkoxybenzyl esters linked to the resin are generally used.Deprotection and cleavage are generally accomplished using TFA.

[0142] Those of ordinary skill in the art will recognize that, in solidphase synthesis, deprotection and coupling reactions must go tocompletion and the side-chain blocking groups must be stable throughoutthe entire synthesis. In addition, solid phase synthesis is generallymost suitable when peptides are to be made on a small scale.

[0143] Acetylation of the N-terminus can be accomplished by reacting thefinal peptide with acetic anhydride before cleavage from the resin.C-amidation is accomplished using an appropriate resin such asmethylbenzhydrylamine resin using the Boc technology.

[0144] Following synthesis of a linear peptide, with or withoutN-acetylation and/or C-amidation, cyclization may be achieved if desiredby any of a variety of techniques well known in the art. Within oneembodiment, a bond may be generated between reactive amino acid sidechains. For example, a disulfide bridge may be formed from a linearpeptide comprising two thiol-containing residues by oxidizing thepeptide using any of a variety of methods. Within one such method, airoxidation of thiols can generate disulfide linkages over a period ofseveral days using either basic or neutral aqueous media. The peptide isused in high dilution to minimize aggregation and intermolecular sidereactions. This method suffers from the disadvantage of being slow buthas the advantage of only producing H₂O as a side product.Alternatively, strong oxidizing agents such as 12 and K₃Fe(CN)₆ can beused to form disulfide linkages. Those of ordinary skill in the art willrecognize that care must be taken not to oxidize the sensitive sidechains of Met, Tyr, Trp or His. Cyclic peptides produced by this methodrequire purification using standard techniques, but this oxidation isapplicable at acid pHs. Oxidizing agents also allow concurrentdeprotection/oxidation of suitable S-protected linear precursors toavoid premature, nonspecific oxidation of free cysteine.

[0145] DMSO, unlike I₂ and K₃Fe(CN)₆, is a mild oxidizing agent whichdoes not cause oxidative side reactions of the nucleophilic amino acidsmentioned above. DMSO is miscible with H₂O at all concentrations, andoxidations can be performed at acidic to neutral pHs with harmlessbyproducts. Methyltrichlorosilane-diphenylsulfoxide may alternatively beused as an oxidizing agent, for concurrent deprotection/oxidation ofS-Acm, S-Tacm or S-t-Bu of cysteine without affecting other nucleophilicamino acids. There are no polymeric products resulting fromintermolecular disulfide bond formation. Suitable thiol-containingresidues for use in such oxidation methods include, but are not limitedto, cysteine, β,β-dimethyl cysteine (penicillamine or Pen),β,β-tetramethylene cysteine (Tmc), β,β-pentamethylene cysteine (Pmc),β-mercaptopropionic acid (Mpr), β,β-pentamethylene-β-mercaptopropionicacid (Pmp), 2-mercaptobenzene, 2-mercaptoaniline and 2-mercaptoproline.Peptides containing such residues are illustrated by the followingrepresentative formulas, in which the nonclassical cadherin isOB-cadherin, the underlined portion is cyclized, N-acetyl groups areindicated by N—Ac and C-terminal amide groups are represented by —NH₂:i) N-Ac-Cys-ASP-Asp-Lys-Cys-NH₂ (SEQ ID NO:669) ii)N-Ac-Cys-Ile-Asp-Asp-Lys-Ser-Gly-Cys-NH₂ (SEQ ID NO:676) iii)N-Ac-Cys-Ile-Asp-Asp-Lys-Cys-NH₂ (SEQ ID NO:670) iv)N-AC-Cys-Asp-Asp-Lys-Ser-Cys-NH₂ (SEQ ID NO:671) v)N-Ac-Cys-IIe-Asp-Asp-Lys-Ser-Cys-NH₂ (SEQ ID NO:673) vi)N-Ac-Cys-Asp-Asp-Lys-Ser-Cys-OH (SEQ ID NO:671) vii)H-Cys-Ile-Asp-Asp-Lys-Ser-Cys-NH₂ (SEQ ID NO:673) viii)N-Ac-Cys-Asp-Asp-Lys-Pen-NH₂ (SEQ ID NO:71) ix)N-Ac-Cys-Phe-Val-Ile-Asp-Asp-Lys-Ser-Gly-Cys-NH₂ (SEQ ID NO:680) x)N-Ac-Cys-Ile-Phe-Val-Ile-Asp-Asp-Lys-Ser-Gly-Cys-NH₂ (SEQ ID NO:683) xi)N-Ac-Ile-Tmc-Val-Ile-Asp-Asp-Lys-Ser-Cys-Glu-NH₂ (SEQ ID NO:53) xii)N-Ac-Ile-Pmc-Val-Ile-Asp-Asp-Lys-Ser-GIy-Cys-NH₂ (SEQ ID NO:54) xiii)Mpr-VaI-Ile-Asp-Asp-Lys-Ser-Gly-Cys-NH₂ (SEQ ID NO:55) xiv)Pmp-Val-Ile-Asp-Asp-Lys-Ser-Gly-Cys-NH₂ (SEQ ID NO:56)

[0146] It will be readily apparent to those of ordinary skill in the artthat, within each of these representative formulas, any of the abovethiol-containing residues may be employed in place of one or both of thethiol-containing residues recited. Similar formulas comprising differentnonclassical cadherin CAR sequences may be generated by those ofordinary skill in the art, based on the CAR sequences provided herein.

[0147] Within another embodiment, cyclization may be achieved by amidebond formation. For example, a peptide bond may be formed betweenterminal functional groups (i.e., the amino and carboxy termini of alinear peptide prior to cyclization). One such cyclic peptide comprisingan OB-cadherin CAR sequence is IDDKSG (SEQ ID NO:717) with or without anN-terminal acetyl group and/or a C-terminal amide. Within another suchembodiment, the linear peptide comprises a D-amino acid (e.g., DDKsS;SEQ ID NO:57). Alternatively, cyclization may be accomplished by linkingone terminus and a residue side chain or using two side chains, as inKDDKD (SEQ ID NO:697) or KIDDKSGD (SEQ ID NO:704), with or without anN-terminal acetyl group and/or a C-terminal amide. Residues capable offorming a lactam bond include lysine, ornithine (Orn), α-amino adipicacid, m-aminomethylbenzoic acid, α,β-diaminopropionic acid, glutamate oraspartate.

[0148] Methods for forming amide bonds are well known in the art and arebased on well established principles of chemical reactivity. Within onesuch method, carbodiimide-mediated lactam formation can be accomplishedby reaction of the carboxylic acid with DCC, DIC, EDAC or DCCl,resulting in the formation of an O-acylurea that can be reactedimmediately with the free amino group to complete the cyclization. Theformation of the inactive N-acylurea, resulting from O→N migration, canbe circumvented by converting the O-acylurea to an active ester byreaction with an N-hydroxy compound such as 1-hydroxybenzotriazole,1-hydroxysuccinimide, 1-hydroxynorbornene carboxamide or ethyl2-hydroximino-2-cyanoacetate. In addition to minimizing O→N migration,these additives also serve as catalysts during cyclization and assist inlowering racemization. Alternatively, cyclization can be performed usingthe azide method, in which a reactive azide intermediate is generatedfrom an alkyl ester via a hydrazide. Hydrazinolysis of the terminalester necessitates the use of a t-butyl group for the protection of sidechain carboxyl functions in the acylating component. This limitation canbe overcome by using diphenylphosphoryl acid (DPPA), which furnishes anazide directly upon reaction with a carboxyl group. The slow reactivityof azides and the formation of isocyanates by their disproportionationrestrict the usefulness of this method. The mixed anhydride method oflactam formation is widely used because of the facile removal ofreaction by-products. The anhydride is formed upon reaction of thecarboxylate anion with an alkyl chloroformate or pivaloyl chloride. Theattack of the amino component is then guided to the carbonyl carbon ofthe acylating component by the electron donating effect of the alkoxygroup or by the steric bulk of the pivaloyl chloride t-butyl group,which obstructs attack on the wrong carbonyl group. Mixed anhydrideswith phosphoric acid derivatives have also been successfully used.Alternatively, cyclization can be accomplished using activated esters.The presence of electron withdrawing substituents on the alkoxy carbonof esters increases their susceptibility to aminolysis. The highreactivity of esters of p-nitrophenol, N-hydroxy compounds andpolyhalogenated phenols has made these “active esters” useful in thesynthesis of amide bonds. The last few years have witnessed thedevelopment of benzotriazolyloxytris-(dimethylamino)phosphoniumhexafluorophosphonate (BOP) and its congeners as advantageous couplingreagents. Their performance is generally superior to that of the wellestablished carbodiimide amide bond formation reactions.

[0149] Within a further embodiment, a thioether linkage may be formedbetween the side chain of a thiol-containing residue and anappropriately derivatized α-amino acid. By way of example, a lysine sidechain can be coupled to bromoacetic acid through the carbodiimidecoupling method (DCC, EDAC) and then reacted with the side chain of anyof the thiol containing residues mentioned above to form a thioetherlinkage. In order to form dithioethers, any two thiol containingside-chains can be reacted with dibromoethane and diisopropylamine inDMF. Examples of thiol-containing linkages are shown below:

[0150] Cyclization may also be achieved using δ₁,δ₁-Ditryptophan (i.e.,Ac-Trp-Gly-Gly-Trp-OMe) (SEQ ID NO:58), as shown below:

[0151] Representative structures of cyclic peptides comprisingOB-cadherin CAR sequences are provided in FIGS. 4A-4C. The structuresand formulas recited herein are provided solely for the purpose ofillustration, and are not intended to limit the scope of the cyclicpeptides described herein.

[0152] For longer modulating agents, recombinant methods are preferredfor synthesis. Within such methods, all or part of a modulating agentcan be synthesized in living cells, using any of a variety of expressionvectors known to those of ordinary skill in the art to be appropriatefor the particular host cell. Suitable host cells may include bacteria,yeast cells, mammalian cells, insect cells, plant cells, algae and otheranimal cells (e.g., hybridoma, CHO, myeloma). The DNA sequencesexpressed in this manner may encode portions of a nonclassical cadherinor other adhesion molecule, or may encode a peptide comprising anonclassical cadherin analogue or an antibody fragment that specificallybinds to a nonclassical cadherin CAR sequence. Such DNA sequences may beprepared based on known cDNA or genomic sequences, or from sequencesisolated by screening an appropriate library with probes designed basedon the sequences of known nonclassical cadherins. Such screens maygenerally be performed as described in Sambrook et al., MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratories, ColdSpring Harbor, N. Y., 1989 (and references cited therein). Polymerasechain reaction (PCR) may also be employed, using oligonucleotide primersin methods well known in the art, to isolate nucleic acid moleculesencoding all or a portion of an endogenous adhesion molecule. Togenerate a nucleic acid molecule encoding a desired modulating agent, anendogenous cadherin sequence may be modified using well knowntechniques. For example, portions encoding one or more CAR sequences maybe joined, with or without separation by nucleic acid regions encodinglinkers, as discussed above. Alternatively, portions of the desirednucleic acid sequences may be synthesized using well known techniques,and then ligated together to form a sequence encoding the modulatingagent.

[0153] As noted above, polynucleotides may also function as modulatingagents. In general, such polynucleotides should be formulated to permitexpression of a polypeptide modulating agent following administration toa mammal. Such formulations are particularly useful for therapeuticpurposes, as described below. Those of ordinary skill in the art willappreciate that there are many ways to achieve expression of apolynucleotide within a mammal, and any suitable method may be employed.For example, a polynucleotide may be incorporated into a viral vectorsuch as, but not limited to, adenovirus, adeno-associated virus,retrovirus, or vaccinia or other pox virus (e.g., avian pox virus).Techniques for incorporating DNA into such vectors are well known tothose of ordinary skill in the art. A retroviral vector may additionallytransfer or incorporate a gene for a selectable marker (to aid in theidentification or selection of transfected cells) and/or a targetingmoiety, such as a gene that encodes a ligand for a receptor on aspecific target cell, to render the vector target specific. Targetingmay also be accomplished using an antibody, by methods known to those ofordinary skill in the art. Other formulations for polynucleotides fortherapeutic purposes include colloidal dispersion systems, such asmacromolecule complexes, nanocapsules, microspheres, beads, andlipid-based systems including oil-in-water emulsions, micelles, mixedmicelles, and liposomes. A preferred colloidal system for use as adelivery vehicle in vitro and in vivo is a liposome (i.e., an artificialmembrane vesicle). The preparation and use of such systems is well knownin the art.

[0154] As noted above, a modulating agent may additionally, oralternatively, comprise a substance such as an antibody orantigen-binding fragment thereof, that specifically binds to anonclassical cadherin CAR sequence. As used herein, a substance is saidto “specifically bind” to a nonclassical cadherin CAR sequence (with orwithout flanking amino acids) if it reacts at a detectable level with apeptide containing that sequence, and does not react detectably withpeptides containing a different CAR sequence or a sequence in which theorder of amino acid residues in the cadherin CAR sequence and/orflanking sequence is altered. Such antibody binding properties maygenerally be assessed using an ELISA, which may be readily performed bythose of ordinary skill in the art and is described, for example, byNewton et al., Develop. Dynamics 197:1-13, 1993.

[0155] Polyclonal and monoclonal antibodies may be raised against anonclassical cadherin CAR sequence using conventional techniques. See,e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold SpringHarbor Laboratory, 1988. In one such technique, an immunogen comprisingthe CAR sequence is initially injected into any of a wide variety ofmammals (e.g., mice, rats, rabbits, sheep or goats). The smallerimmunogens (i.e., less than about 20 amino acids) should be joined to acarrier protein, such as bovine serum albumin or keyhole limpethemocyanin. Following one or more injections, the animals are bledperiodically. Polyclonal antibodies specific for the CAR sequence maythen be purified from such antisera by, for example, affinitychromatography using the modulating agent or antigenic portion thereofcoupled to a suitable solid support.

[0156] Monoclonal antibodies specific for a nonclassical cadherinsequence may be prepared, for example, using the technique of Kohler andMilstein, Eur. J. Immunol. 6:511-519, 1976, and improvements thereto.Briefly, these methods involve the preparation of immortal cell linescapable of producing antibodies having the desired specificity fromspleen cells obtained from an animal immunized as described above. Thespleen cells are immortalized by, for example, fusion with a myelomacell fusion partner, preferably one that is syngeneic with the immunizedanimal. Single colonies are selected and their culture supernatantstested for binding activity against the modulating agent or antigenicportion thereof. Hybridomas having high reactivity and specificity arepreferred.

[0157] Monoclonal antibodies may be isolated from the supernatants ofgrowing hybridoma colonies, with or without the use of varioustechniques known in the art to enhance the yield. Contaminants may beremoved from the antibodies by conventional techniques, such aschromatography, gel filtration, precipitation and extraction. Antibodieshaving the desired activity may generally be identified usingimmunofluorescence analyses of tissue sections, cell or other sampleswhere the target cadherin is localized.

[0158] Within certain embodiments, the use of antigen-binding fragmentsof antibodies may be preferred. Such fragments include Fab fragments,which may be prepared using standard techniques. Briefly,immunoglobulins may be purified from rabbit serum by affinitychromatography on Protein A bead columns (Harlow and Lane, Antibodies: ALaboratory Manual, Cold Spring Harbor Laboratory, 1988; see especiallypage 309) and digested by papain to yield Fab and Fc fragments. The Faband Fc fragments may be separated by affinity chromatography on proteinA bead columns (Harlow and Lane, 1988, pages 628-29). Evaluation ofModulating Agent Activity

[0159] Modulating agents as described above are capable of modulatingone or more nonclassical cadherin-mediated functions. An initial screenfor such activity may be performed by evaluating the ability of amodulating agent to bind to a nonclassical cadherin using any bindingassay known to those of ordinary skill in the art. For example, aPharmacia Biosensor machine may be used, as discussed in Jonsson et al.,Biotechniques 11:520-27, 1991. For example, a modulating agent maycomprise a CAR sequence that binds to a nonclassical cadherin. Aspecific example of a technology that measures the interaction ofpeptides with molecules can be found in Williams et al., J. Biol. Chem.272, 22349-22354, 1997. Alternatively, real-time BIA (BiomolecularInteraction Analysis) uses the optical phenomenon surface plasmonresonance to monitor biomolecular interactions. The detection dependsupon changes in the mass concentration of macromolecules at thebiospecific interface, which in turn depends upon the immobilization oftest molecule or peptide (referred to as the ligand) to the surface of aBiosensor chip, followed by binding of the interacting molecule(referred to as the analyte) to the ligand. Binding to the chip ismeasured in real-time in arbitrary units of resonance (RU).

[0160] By way of example, surface plasmon resonance experiments may becarried out using a BIAcore X^(TM) Biosensor (Pharmacia Ltd., BIAcore,Uppsala, Sweden). Parallel flow cells of CM 5 sensor chips may bederivatized, using the amine coupling method, with streptavidin (200μg/ml) in 10 mM Sodium Acetate, pH 4.0, according to the manufacturer'sprotocol. Approximately 2100-2600 resonance units (RU) of ligand may beimmobilized, corresponding to a concentration of about 2.1-2.6 ng/mm².The chips may then coated be with nonclassical cadherin derivatized tobiotin. Any non-specifically bound protein is removed.

[0161] To determine binding, test analytes (e.g., peptides containingthe nonclassical cadherin CAR sequence) may be placed in running bufferand passed simultaneously over test and control flow cells. After aperiod of free buffer flow, any analyte remaining bound to the surfacemay be removed with, for example, a pulse of 0.1% SDS bringing thesignal back to baseline. Specific binding to the derivatized sensorchips may be determined automatically by the system by subtraction oftest from control flow cell responses. In general, a modulating agentbinds to a nonclassical cadherin at a detectable level within such asassay. The level of binding is preferably at least that observed for thefull length nonclassical cadherin under similar conditions.

[0162] The ability to modulate a nonclassical cadherin-mediated functionmay be evaluated using any of a variety of in vitro assays designed tomeasure the effect of the peptide on a response that is generallymediated by the nonclassical cadherin. As noted above, modulating agentsmay be capable of enhancing or inhibiting a nonclassicalcadherin-mediated function.

[0163] Certain nonclassical cadherins are associated with adhesion ofparticular cell types (e.g., cancer cells). The ability of an agent tomodulate cell adhesion may generally be evaluated in vitro by assayingthe effect on adhesion between appropriate cells. In general, amodulating agent is an inhibitor of cell adhesion if contact of the testcells with the modulating agent results in a discernible disruption ofcell adhesion. Modulating agents that enhance cell adhesion (e.g.,agents comprising multiple nonclassical cadherin CAR sequences and/ornonclassical cadherin CAR sequences linked to a support material) areconsidered to be modulators of cell adhesion if they are capable ofpromoting cell adhesion, as judged by plating assays to assess celladhesion to a modulating agent attached to a support material, such astissue culture plastic.

[0164] Within certain cell adhesion assays, the addition of a modulatingagent to cells that express a nonclassical cadherin results indisruption of cell adhesion. A “nonclassical cadherin-expressing cell,”as used herein, may be any type of cell that expresses a nonclassicalcadherin at a detectable level, using standard techniques such asimmunocytochemical protocols (e.g., Blaschuk and Farookhi, Dev. Biol.136:564-567, 1989). For example, such cells may be plated under standardconditions that, in the absence of modulating agent, permit celladhesion. In the presence of modulating agent (e.g., 1 mg/mL),disruption of cell adhesion may be determined visually within 24 hours,by observing retraction of the cells from one another and thesubstratum.

[0165] Suitable cells for use within such assays may be any of a varietyof cells that express the nonclassical cadherin of interest. Certaincells express one or more cadherins endogenously. For example,OB-cadherin-expressing cells include stromal, osteoblast and/or cancercells. Cadherin-5 is expressed by endothelial cells, and cadherin-6expression is associated with, for example, kidney tumor cells.Accordingly, such cell types may be used to assess the effect ofmodulating agents directed against OB-cadherin or cadherin-5 CARsequences. In general, MDCK cells or keratinocytes may be used toevaluate desmocollin- or desmoglein-mediated cell adhesion. Neural cellsmay be used to evaluate protocadherin, cnr, PB-cadherin and type IIcadherin function. It will be apparent that other cells may also be usedwithin such assays, provided that the cells express the nonclassicalcadherin of interest.

[0166] Alternatively, cells that do not naturally express a cadherin maybe used within such assays. Such cells may be stably transfected with apolynucleotide (e.g., a cDNA) encoding a cadherin of interest, such thatthe cadherin is expressed on the surface of the cell. Expression of thecadherin may be confirmed by assessing adhesion of the transfectedcells, in conjunction with immunocytochemical techniques usingantibodies directed against the cadherin of interest. The stablytransfected cells that aggregate, as judged by light microscopy,following transfection express sufficient levels of the nonclassicalcadherin. Preferred cells for use in such assays include L cells, whichdo not detectably adhere and do not express any cadherin (Nagafuchi etal., Nature 329:341-343, 1987). Following transfection of L cells with acDNA encoding a cadherin, aggregation is observed. Modulating agentsthat detectably inhibit such aggregation may be used to modulatefunctions mediated by the nonclassical cadherin. Such assays have beenused for numerous nonclassical cadherins, including OB-cadherin (Okazakiet al., J. Biol. Chem. 269:12092-98, 1994), cadherin-5 (Breier et al.,Blood 87:630-641, 1996), cadherin-6 (Mbalaviele et al., J. Cell. Biol.141:1467-1476, 1998), cadherin-8 (Kido et al., Genomics 48:186-194,1998), cadherin-15 (Shimoyama et al., J. Biol. Chem. 273:10011-10018,1998), PB-cadherin (Sugimoto et al., J. Biol. Chem. 271:11548-11556,1996), LI-cadherin (Kreft et al., J. Cell. Biol. 136:1109-1121, 1997),protocadherin 42 and 43 (Sano et al., EMBO J. 12:2249-2256, 1993) anddesmosomal cadherins (Marcozzi et al., J. Cell. Sci. 111:495-509, 1998).It will be apparent to those of ordinary skill in the art that assaysmay be performed in a similar manner for other nonclassical cadherins.

[0167] Transfection of cells for use in cell adhesion assays may beperformed using standard techniques and published cadherin sequences.For example, sequences of nonclassical cadherins may be found withinreferences cited herein and in the GenBank database. GenBank accessionnumbers for certain nonclassical cadherins include: X59796 (humancadherin-5); D31784 (human cadherin-6); D42150 (chicken cadherin-7);L34060 (human cadherin-8); L34056 (human OB cadherin); L34057 (humancadherin-12); U59325 (human cadherin-14); D83542 (human cadherin-15);D83348 and D88349 (rat PB-cadherin); X83228 (human LI-cadherin); L34058(human T cadherin); LI 1373 (human protocadherin 43); AF029343 (humanprotocadherin 68); X56654 (human desmoglein 1); Z26317 and S64273 (humandesmoglein 2); X72925 (human desmocollin 1); X56807 (human desmocollin2); X83929 (human desmocollin 3); D17427 (human desmocollin 4); D86916(mouse cadherin-related neuronal receptor 1); D86917 (mousecadherin-related neuronal receptor 2); AB008178 (mouse cadherin-relatedneuronal receptor 3); AB008180 (mouse cadherin-related neuronal receptor5); AB008181 (mouse cadherin-related neuronal receptor 6); AB008182(mouse cadherin-related neuronal receptor 7); AB008183 (mousecadherin-related neuronal receptor 8).

[0168] By way of example, an assay for evaluating a modulating agent forthe ability to inhibit an OB-cadherin mediated function may employMDA-231 human breast cancer cells. According to a representativeprocedure, the cells may be plated at 10-20,000 cells per 35 mm tissueculture flasks containing DMEM with 5% FCS and sub-cultured periodically(Sommers et al., Cell Growth Diffn 2:365-72, 1991). Cells may beharvested and replated in 35 mm tissue culture flasks containing 1 mmcoverslips and incubated until 50-65% confluent (24-36 hours). At thistime, coverslips may be transferred to a 24-well plate, washed once withfresh DMEM and exposed to modulating agent at a concentration of, forexample, 1 mg/mL for 24 hours. Fresh modulating agent may then be added,and the cells left for an additional 24 hours. Cells may be fixed with2% paraformaldehyde for 30 minutes and then washed three times with PBS.Coverslips can be mounted and viewed by phase contrast microscopy.

[0169] In the absence of modulating agent, MDA-231 cells display anepithelial-like morphology and are well attached to the substratum.MDA-231 cells that are treated with a modulating agent that disruptsOB-cadherin mediated cell adhesion may assume a round shape and becomeloosely attached to the substratum within 48 hours of treatment with 1mg/mL of modulating agent.

[0170] It will be apparent that similar assays may be performed toassess a modulating agent for the ability to inhibit cell adhesionmediated by other nonclassical cadherins, using cells appropriate forthe nonclassical cadherin of interest. In general, a modulating agentthat is derived from a particular nonclassical cadherin CAR sequence(i.e., comprises such a CAR sequence, or an analog or mimetic thereof,or an antibody that specifically recognizes such a CAR sequence) andthat modulates adhesion of a cell that expresses the same nonclassicalcadherin is considered to modulate a function mediated by thenonclassical cadherin.

[0171] Other assays may be used to assess the effect of a modulatingagent on specific nonclassical cadherin-mediated functions. For example,modulating agents that inhibit interactions of certain nonclassicalcadherins (e.g., OB-cadherin, cadherin-5, desmogleins and desmocollins)may enhance skin permeability. This ability may be assessed byevaluating, for example, the effect of a modulating agent onpermeability of adherent epithelial and/or endothelial cell layers(e.g., human skin). Such skin may be derived from a natural source ormay be synthetic. Human abdominal skin for use in such assays maygenerally be obtained from humans at autopsy within 24 hours of death.Briefly, a modulating agent (e.g., 500 μg/ml) and a test marker (e.g.,the fluorescent markers Oregon Green™ and Rhodamine Green™ Dextran) maybe dissolved in a sterile buffer (e.g., phosphate buffer, pH 7.2), andthe ability of the marker to penetrate through the skin and into areceptor fluid (e.g., phosphate buffer) may be measured using a FranzCell apparatus (Franz, Curr. Prob. Dermatol. 7:58-68, 1978; Franz, J.Invest. Dermatol. 64:190-195, 1975). The penetration of the markersthrough the skin may be assessed at, for example, 6, 12, 24, 36, and 48hours after the start of the experiment. In general, a modulating agentthat enhances the permeability of human skin results in a statisticallysignificant increase in the amount of marker in the receptor compartmentafter 6-48 hours in the presence of 500 μg/mL modulating agent.

[0172] Certain other nonclassical cadherins (e.g., cadherin-7,cadherin-8, cadherin-12, cadherin-14, cadherin-15, T-cadherin,PB-cadherin, protocadherins and cnrs) may be involved in mediatingneurite growth. Agents that modulate such a function may be evaluatedusing a neurite outgrowth assay. Within one such assay, neurons may becultured on a monolayer of cells (e.g., 3T3 cells) that express anonclassical cadherin. Neurons grown on such cells (under suitableconditions and for a sufficient period of time) extend neurites that aretypically, on average, twice as long as neurites extended from neuronscultured on 3T3 cells that do not express the nonclassical cadherin.Briefly, monolayers of control 3T3 fibroblasts and 3T3 fibroblasts thatexpress a nonclassical cadherin may be established by overnight cultureof 80,000 cells in individual wells of an 8-chamber well tissue cultureslide. 3000 cerebellar neurons isolated from post-natal day 3 mousebrains may be cultured for 18 hours on the various monolayers in controlmedia (SATO/2%FCS), or media supplemented with various concentrations ofthe modulating agent or control peptide. The cultures may then be fixedand stained for GAP43 which specifically binds to the neurons and theirneurites. The length of the longest neurite on each GAP43 positiveneuron may be measured by computer assisted morphometry.

[0173] A modulating agent may inhibit or enhance such neurite outgrowth.Under the conditions described above, the presence of 500 μg/mL of amodulating agent that disrupts neural cell adhesion should result in adecrease in the mean neurite length by at least 50%, relative to thelength in the absence of modulating agent or in the presence of anegative control peptide. Alternatively, the presence of 500 μg/mL of amodulating agent that enhances neural cell adhesion should result in anincrease in the mean neurite length by at least 50%.

[0174] Transfection of cells for use in a neurite outgrowth assay may beperformed using standard techniques and published cadherin sequences.For example, sequences of nonclassical cadherins may be found withinreferences cited herein and in the GenBank database. GenBank accessionnumbers for these cadherins are recited above.

[0175] Certain modulating agents (e.g., peptides that containVE-cadherin and/or OB-cadherin CAR sequences, or analogues or mimeticsthereof) may inhibit angiogenesis. The effect of a particular modulatingagent on angiogenesis may generally be determined by evaluating theeffect of the agent on blood vessel formation. Such a determination maygenerally be performed, for example, using a chick chorioallantoicmembrane assay (Iruela-Arispe et al., Molecular Biology of the Cell6:327-343, 1995). Briefly, a modulating agent may be embedded in a meshcomposed of vitrogen at one or more concentrations (e.g., ranging fromabout 1 to 100 μg/mlsh). The mesh(es) may then be applied to chickchorioallantoic membranes. After 24 hours, the effect of the modulatingagent may be determined using computer assisted morphometric analysis. Amodulating agent should inhibit angiogenesis by at least 25% at aconcentration of 33 μg/mlsh.

[0176] A myoblast fusion assay may be used as a functional assay foragents that modulate cadherin-15 function. Cadherin-15 has been shown tomediate the fusion of muscle cells into mature muscle fibers in vitro.Briefly, to perform such an assay, myoblasts may be grown in a dish,differentiation is induced, and modulating agent is added. The effect onfusion is then evaluated. In general, a modulating agent that inhibitscadherin-15 function results in a statistically significant decrease inmyoblast fusion in the presence of 1 mg/mL modulating agent. Such assaysmay be performed as described by Pouliot et al., Dev. Biol. 141:292-298,1990.

Modulating Agent Modification and Formulations

[0177] A modulating agent as described herein may, but need not, belinked to one or more additional molecules. In particular, as discussedbelow, it may be beneficial for certain applications to link multiplemodulating agents (which may, but need not, be identical) to a supportmaterial, such as a single molecule (e.g., keyhole limpet hemocyanin) ora solid support, such as a polymeric matrix (which may be formulated asa membrane or microstructure, such as an ultra thin film), a containersurface (e.g., the surface of a tissue culture plate or the interiorsurface of a bioreactor), or a bead or other particle, which may beprepared from a variety of materials including glass, plastic orceramics. For certain applications, biodegradable support materials arepreferred, such as cellulose and derivatives thereof, collagen, spidersilk or any of a variety of polyesters (e.g., those derived from hydroxyacids and/or lactones) or sutures (see U.S. Pat. No. 5,245,012). Withincertain embodiments, modulating agents and molecules comprising otherCAR sequence(s) (e.g., an HAV or RGD sequence) may be attached to asupport such as a polymeric matrix, preferably in an alternatingpattern.

[0178] Suitable methods for linking a modulating agent to a supportmaterial will depend upon the composition of the support and theintended use, and will be readily apparent to those of ordinary skill inthe art. Attachment may generally be achieved through noncovalentassociation, such as adsorption or affinity or, preferably, via covalentattachment (which may be a direct linkage between a modulating agent andfunctional groups on the support, or may be a linkage by way of across-linking agent). Attachment of a modulating agent by adsorption maybe achieved by contact, in a suitable buffer, with a solid support for asuitable amount of time. The contact time varies with temperature, butis generally between about 5 seconds and 1 day, and typically betweenabout 10 seconds and 1 hour.

[0179] Covalent attachment of a modulating agent to a molecule or solidsupport may generally be achieved by first reacting the support materialwith a bifunctional reagent that will also react with a functionalgroup, such as a hydroxyl or amino group, on the modulating agent. Forexample, a modulating agent may be bound to an appropriate polymericsupport or coating using benzoquinone, by condensation of an aldehydegroup on the support with an amine and an active hydrogen on themodulating agent or by condensation of an amino group on the supportwith a carboxylic acid on the modulating agent. A preferred method ofgenerating a linkage is via amino groups using glutaraldehyde. Amodulating agent may be linked to cellulose via ester linkages.Similarly, amide linkages may be suitable for linkage to other moleculessuch as keyhole limpet hemocyanin or other support materials. Multiplemodulating agents and/or molecules comprising other CAR sequences may beattached, for example, by random coupling, in which equimolar amounts ofsuch molecules are mixed with a matrix support and allowed to couple atrandom.

[0180] Although modulating agents as described herein may preferentiallybind to specific tissues or cells, and thus may be sufficient to targeta desired site in vivo, it may be beneficial for certain applications toinclude an additional targeting agent. Accordingly, a targeting agentmay also, or alternatively, be linked to a modulating agent tofacilitate targeting to one or more specific tissues. As used herein, a“targeting agent,” may be any substance (such as a compound or cell)that, when linked to a modulating agent enhances the transport of themodulating agent to a target tissue, thereby increasing the localconcentration of the modulating agent. Targeting agents includeantibodies or fragments thereof, receptors, ligands and other moleculesthat bind to cells of, or in the vicinity of, the target tissue. Knowntargeting agents include serum hormones, antibodies against cell surfaceantigens, lectins, adhesion molecules, tumor cell surface bindingligands, steroids, cholesterol, lymphokines, fibrinolytic enzymes andthose drugs and proteins that bind to a desired target site. Among themany monoclonal antibodies that may serve as targeting agents areanti-TAC, or other interleukin-2 receptor antibodies; 9.2.27 andNR-ML-05, reactive with the 250 kilodalton human melanoma-associatedproteoglycan; and NR-LU-10, reactive with a pancarcinoma glycoprotein.An antibody targeting agent may be an intact (whole) molecule, afragment thereof, or a functional equivalent thereof. Examples ofantibody fragments are F(ab′)2, -Fab′, Fab and F[v] fragments, which maybe produced by conventional methods or by genetic or proteinengineering. Linkage is generally covalent and may be achieved by, forexample, direct condensation or other reactions, or by way of bi- ormulti-functional linkers.

[0181] For certain embodiments, it may be beneficial to also, oralternatively, link a drug to a modulating agent. As used herein, theterm “drug” refers to any bioactive agent intended for administration toa mammal to prevent or treat a disease or other undesirable condition.Drugs include hormones, growth factors, proteins, peptides and othercompounds. The use of certain specific drugs within the context of thepresent invention is discussed below.

[0182] Modulating agents as described herein may be present within apharmaceutical composition. A pharmaceutical composition comprises oneor more modulating agents in combination with one or morepharmaceutically or physiologically acceptable carriers, diluents orexcipients. Such compositions may comprise buffers (e.g., neutralbuffered saline or phosphate buffered saline), carbohydrates (e.g.,glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptidesor amino acids such as glycine, antioxidants, chelating agents such asEDTA or glutathione, adjuvants (e.g., aluminum hydroxide) and/orpreservatives. Within yet other embodiments, compositions of the presentinvention may be formulated as a lyophilizate. One or more modulatingagents (alone or in combination with a targeting agent and/or drug) may,but need not, be encapsulated within liposomes using well knowntechnology. Compositions of the present invention may be formulated forany appropriate manner of administration, including for example,topical, oral, nasal, intravenous, intracranial, intraperitoneal,subcutaneous, or intramuscular administration.

[0183] For certain embodiments, as discussed below, a pharmaceuticalcomposition may further comprise a modulator of cell adhesion that ismediated by one or more molecules other than the particular nonclassicalcadherin. Such modulators may generally be prepared as described above,using one or more CAR sequences and/or antibodies thereto. Suchcompositions are particularly useful for situations in which it isdesirable to inhibit cell adhesion mediated by multiple cell adhesionmolecules, such as other members of the cadherin gene superfamily suchas the classical cadherins (e.g., N-cadherin and E-cadherin); integrins;occludin; claudins; N-CAM and/or extracellular matrix proteins such aslaminin, fibronectin, collagens, vitronectin, entactin and tenascin.

[0184] A pharmaceutical composition may also, or alternatively, containone or more drugs, which may be linked to a modulating agent or may befree within the composition. Virtually any drug may be administered incombination with a modulating agent as described herein, for a varietyof purposes as described below. Examples of types of drugs that may beadministered with a modulating agent include analgesics, anesthetics,antianginals, antifungals, antibiotics, anticancer drugs (e.g., taxol ormitomycin C), antiinflammatories (e.g., ibuprofen and indomethacin),anthelmintics, antidepressants, antidotes, antiemetics, antihistamines,antihypertensives, antimalarials, antimicrotubule agents (e.g.,colchicine or vinca alkaloids), antimigraine agents, antimicrobials,antiphsychotics, antipyretics, antiseptics, anti-signaling agents (e.g.,protein kinase C inhibitors or inhibitors of intracellular calciummobilization), antiarthritics, antithrombin agents, antituberculotics,antitussives, antivirals, appetite suppressants, cardioactive drugs,chemical dependency drugs, cathartics, chemotherapeutic agents,coronary, cerebral or peripheral vasodilators, contraceptive agents,depressants, diuretics, expectorants, growth factors, hormonal agents,hypnotics, immunosuppression agents, narcotic antagonists,parasympathomimetics, sedatives, stimulants, sympathomimetics, toxins(e.g., cholera toxin), tranquilizers and urinary antiinfectives.

[0185] For imaging purposes, any of a variety of diagnostic agents maybe incorporated into a pharmaceutical composition, either linked to amodulating agent or free within the composition. Diagnostic agentsinclude any substance administered to illuminate a physiologicalfunction within a patient, while leaving other physiological functionsgenerally unaffected. Diagnostic agents include metals, radioactiveisotopes and radioopaque agents (e.g., gallium, technetium, indium,strontium, iodine, barium, bromine and phosphorus-containing compounds),radiolucent agents, contrast agents, dyes (e.g., fluorescent dyes andchromophores) and enzymes that catalyze a calorimetric or fluorometricreaction. In general, such agents may be attached using a variety oftechniques as described above, and may be present in any orientation.

[0186] The compositions described herein may be administered as part ofa sustained release formulation (i.e., a formulation such as a capsuleor sponge that effects a slow release of modulating agent followingadministration). Such formulations may generally be prepared using wellknown technology and administered by, for example, oral, rectal orsubcutaneous implantation, or by implantation at the desired targetsite. Sustained-release formulations may contain a modulating agentdispersed in a carrier matrix and/or contained within a reservoirsurrounded by a rate controlling membrane (see, e.g., European PatentApplication 710,491 A). Carriers for use within such formulations arebiocompatible, and may also be biodegradable; preferably the formulationprovides a relatively constant level of modulating agent release. Theamount of modulating agent contained within a sustained releaseformulation depends upon the site of implantation, the rate and expectedduration of release and the nature of the condition to be treated orprevented.

[0187] Pharmaceutical compositions of the present invention may beadministered in a manner appropriate to the disease to be treated (orprevented). Appropriate dosages and a suitable duration and frequency ofadministration will be determined by such factors as the condition ofthe patient, the type and severity of the patient's disease and themethod of administration. In general, an appropriate dosage andtreatment regimen provides the modulating agent(s) in an amountsufficient to provide therapeutic and/or prophylactic benefit. Withinparticularly preferred embodiments of the invention, a modulating agentor pharmaceutical composition as described herein may be administered ata dosage ranging from 0.001 to 50 mg/kg body weight, preferably from 0.1to 20 mg/kg, on a regimen of single or multiple daily doses. For topicaladministration, a cream typically comprises an amount of modulatingagent ranging from 0.00001% to 1%, preferably 0.0001% to 0.002%. Fluidcompositions typically contain about 10 ng/ml to 5 mg/ml, preferablyfrom about 10 μg to 2 mg/mL modulating agent. Appropriate dosages maygenerally be determined using experimental models and/or clinicaltrials. In general, the use of the minimum dosage that is sufficient toprovide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using assays suitable for thecondition being treated or prevented, which will be familiar to those ofordinary skill in the art.

Modulating Agent Methods of Use

[0188] In general, the modulating agents and compositions describedherein may be used for modulating a function, such as cell adhesion, ofnonclassical cadherin-expressing cells. Such modulation may be performedin vitro and/or in vivo, preferably in a mammal such as a human, usingany method that contacts the nonclassical cadherin-expressing cell withthe modulating agent. As noted above, modulating agents for purposesthat involve the disruption of nonclassical cadherin-mediated.celladhesion may comprise a nonclassical cadherin CAR sequence, multiplenonclassical cadherin CAR sequences in close proximity and/or asubstance (such as an antibody or an antigen-binding fragment thereofthat recognizes a nonclassical cadherin CAR sequence. When it isdesirable to also disrupt cell adhesion mediated by other adhesionmolecules, a modulating agent may additionally comprise one or more CARsequences bound by such adhesion molecules (and/or antibodies orfragments thereof that bind such sequences), preferably separatedfrom.each other and from the nonclassical cadherin CAR sequence bylinkers. As noted above, such linkers may or may not comprise one ormore amino acids. For enhancing cell adhesion, a modulating agent maycontain multiple nonclassical cadherin CAR sequences derived from eithera particular nonclassical cadherin or antibodies (or fragments),preferably separated by linkers, and/or may be linked to a singlemolecule or to a support material as described above. When it isdesirable to also enhance cell adhesion mediated by other adhesionmolecules, a modulating agent may additionally comprise one or more CARsequences bound by such adhesion molecules (and/or antibodies orfragments thereof that bind such sequences), preferably separated fromeach other and from the nonclassical cadherin CAR sequence by linker.

[0189] Certain methods involving the disruption of cell adhesion asdescribed herein have an advantage over prior techniques in that theyblock tumor cell adhesion. As described in greater detail below,modulating agents as described herein may also be used to disrupt orenhance cell adhesion in a variety of other contexts. Within each of themethods described herein, one or more modulating agents may generally beadministered alone, or within a pharmaceutical composition. In eachspecific method described herein, as noted above, a targeting agent maybe employed to increase the local concentration of modulating agent atthe target site.

[0190] Within one aspect, methods are provided in which cell adhesion isdiminished. In one such aspect, the present invention provides methodsfor reducing unwanted cellular adhesion in a mammal by administering amodulating agent as described herein. Unwanted cellular adhesion canoccur, for example, between tumor cells, between tumor cells and normalcells or between normal cells as a result of surgery, injury,chemotherapy, disease, inflammation or other condition jeopardizing cellviability or function. Certain preferred modulating agents for usewithin such methods comprise one or more of the nonclassical CARsequences provided herein. In one particularly preferred embodiment, amodulating agent is further capable of disrupting cell adhesion mediatedby multiple adhesion molecules. Such an agent may comprise, in additionto one or more nonclassical cadherin CAR sequences, CAR sequences suchas the classical cadherin CAR sequence HAV sequence, an RGD sequence,which is bound by integrins, the occludin CAR sequence LYHY (SEQ IDNO:52); and/or the putative claudin CAR sequence IYSY (SEQ ID NO:51),preferably separated from the nonclassical cadherin CAR sequence via alinker. Alternatively, separate modulators of cell adhesion mediated byother adhesion molecules may be administered in conjunction with themodulating agent(s), either within the same pharmaceutical compositionor separately.

[0191] Topical administration of the modulating agent(s) is generallypreferred, but other means may also be employed. Preferably, a fluidcomposition for topical administration (comprising, for example,physiological saline) comprises an amount of modulating agent asdescribed above, and more preferably from 10 μg/mL to 1 mg/mL. Creamsmay generally be formulated as described above. Topical administrationin the surgical field may be given once at the end of surgery byirrigation of the wound or as an intermittent or continuous irrigationwith the use of surgical drains in the post-operative period or by theuse of drains specifically inserted in an area of inflammation, injuryor disease in cases where surgery does not need to be performed.Alternatively, parenteral or transcutaneous administration may be usedto achieve similar results.

[0192] Certain modulating agents as provided herein may be used tofacilitate transdermal drug delivery. Transdermal delivery of drugs is aconvenient and non-invasive method that can be used to maintainrelatively constant blood levels of a drug. In general, to facilitatedrug delivery via the skin, it is necessary to perturb adhesion betweenthe epithelial cells (keratinocytes) and the endothelial cells of themicrovasculature. Using currently available techniques, only small,uncharged molecules may be delivered across skin in vivo. The methodsdescribed herein are not subject to the same degree of limitation.Accordingly, a wide variety of drugs may be transported across theepithelial and endothelial cell layers of skin, for systemic or topicaladministration. Such drugs may be delivered to melanomas or may enterthe blood stream of the mammal for delivery to other sites within thebody.

[0193] To enhance the delivery of a drug through the skin, a modulatingagent as described herein and a drug are contacted with the skinsurface. Certain preferred modulating agents for use within such methodscomprise a CAR sequence (or an analogue or mimetic thereof) ofOB-cadherin, cadherin-5, a desmoglein or a desmocollin. Multifunctionalmodulating agents comprising multiple nonclassical cadherin CARsequences may also be used. Such modulating agents may also, oralternatively, comprise the classical cadherin CAR sequence HAV, thefibronectin CAR sequence RGD, which is recognized by integrins, and/orthe occludin CAR sequence LYHY (SEQ ID NO:52). Alternatively, a separatemodulator of cell adhesion may be administered in conjunction with themodulating agent(s), either within the same pharmaceutical compositionor separately.

[0194] Contact may be achieved by direct application of the modulatingagent, generally within a composition formulated as a cream or gel, orusing any of a variety of skin contact devices for transdermalapplication (such as those described in European Patent Application No.566,816 A; U.S. Pat. No. 5,613,958; U.S. Pat. No. 5,505,956). A skinpatch provides a convenient method of administration (particularly forslow-release formulations). Such patches may contain a reservoir ofmodulating agent and drug separated from the skin by a membrane throughwhich the drug diffuses. Within other patch designs, the modulatingagent and drug may be dissolved or suspended in a polymer or adhesivematrix that is then placed in direct contact with the patient's skin.The modulating agent and drug may then diffuse from the matrix into theskin. Modulating agent(s) and drug(s) may be contained within the samecomposition or skin patch, or may be separately administered, althoughadministration at the same time and site is preferred. In general, theamount of modulating agent administered via the skin varies with thenature of the condition to be treated or prevented, but may vary asdescribed above. Such levels may be achieved by appropriate adjustmentsto the device used, or by applying a cream formulated as describedabove. Transfer of the drug across the skin and to the target tissue maybe predicted based on in vitro studies using, for example, a Franz cellapparatus, and evaluated in vivo by appropriate means that will beapparent to those of ordinary skill in the art. As an example,monitoring of the serum level of the administered drug over timeprovides an easy measure of the drug transfer across the skin.

[0195] Transdermal drug delivery as described herein is particularlyuseful in situations in which a constant rate of drug delivery isdesired, to avoid fluctuating blood levels of a drug. For example,morphine is an analgesic commonly used immediately following surgery.When given intermittently in a parenteral form (intramuscular,intravenous), the patient usually feels sleepy during the first hour, iswell during the next 2 hours and is in pain during the last hour becausethe blood level goes up quickly after the injection and goes down belowthe desirable level before the 4 hour interval prescribed forre-injection is reached. Transdermal administration as described hereinpermits the maintenance of constant levels for long periods of time(e.g., days), which allows adequate pain control and mental alertness atthe same time. Insulin provides another such example. Many diabeticpatients need to maintain a constant baseline level of insulin which isdifferent from their needs at the time of meals. The baseline level maybe maintained using transdermal administration of insulin, as describedherein. Antibiotics may also be administered at a constant rate,maintaining adequate bactericidal blood levels, while avoiding the highlevels that are often responsible for the toxicity (e.g., levels ofgentamycin that are too high typically result in renal toxicity).

[0196] Drug delivery by the methods of the present invention alsoprovide a more convenient method of drug administration. For example, itis often particularly difficult to administer parenteral drugs tonewborns and infants because of the difficulty associated with findingveins of acceptable caliber to catheterize. However, newborns andinfants often have a relatively large skin surface as compared toadults. Transdermal drug delivery permits easier management of suchpatients and allows certain types of care that can presently be givenonly in hospitals to be given at home. Other patients who typically havesimilar difficulties with venous catheterization are patients undergoingchemotherapy or patients on dialysis. In addition, for patientsundergoing prolonged therapy, transdermal administration as describedherein is more convenient than parenteral administration.

[0197] Transdermal administration as described herein also allows thegastrointestinal tract to be bypassed in situations where parenteraluses would not be practical. For example, there is a growing need formethods suitable for administration of therapeutic small peptides andproteins, which are typically digested within the gastrointestinaltract. The methods described herein permit administration of suchcompounds and allow easy administration over long periods of time.Patients who have problems with absorption through theirgastrointestinal tract because of prolonged ileus or specificgastrointestinal diseases limiting drug absorption may also benefit fromdrugs formulated for transdermal application as described herein.

[0198] Further, there are many clinical situations where it is difficultto maintain compliance. For example, patients with mental problems(e.g., patients with Alzheimer's disease or psychosis) are easier tomanage if a constant delivery rate of drug is provided without having torely on their ability to take their medication at specific times of theday. Also patients who simply forget to take their drugs as prescribedare less likely to do so if they merely have to put on a skin patchperiodically (e.g., every 3 days). Patients with diseases that arewithout symptoms, like patients with hypertension, are especially atrisk of forgetting to take their medication as prescribed.

[0199] For patients taking multiple drugs, devices for transdermalapplication such as skin patches may be formulated with combinations ofdrugs that are frequently used together. For example, many heart failurepatients are given digoxin in combination with furosemide. Thecombination of both drugs into a single skin patch facilitatesadministration, reduces the risk of errors (taking the correct pills atthe appropriate time is often confusing to older people), reduces thepsychological strain of taking “so many pills,” reduces skipped dosagebecause of irregular activities and improves compliance.

[0200] The methods described herein are particularly applicable tohumans, but also have a variety of veterinary uses, such as theadministration of growth factors or hormones (e.g., for fertilitycontrol) to an animal.

[0201] As noted above, a wide variety of drugs may be administeredaccording to the methods provided herein. Some examples of drugcategories that may be administered transdermally includeanti-inflammatory drugs (e.g., in arthritis and in other condition) suchas all NSAID, indomethacin, prednisone, etc.; analgesics (especiallywhen oral absorption is not possible, such as after surgery, and whenparenteral administration is not convenient or desirable), includingmorphine, codeine, Demerol, acetaminophen and combinations of these(e.g., codeine plus acetaminophen); antibiotics such as Vancomycin(which is not absorbed by the GI tract and is frequently givenintravenously) or a combination of INH and Rifampicin (e.g., fortuberculosis); anticoagulants such as heparin (which is not wellabsorbed by the GI tract and is generally given parenterally, resultingin fluctuation in the blood levels with an increased risk of bleeding athigh levels and risks of inefficacy at lower levels) and Warfarin (whichis absorbed by the GI tract but cannot be administered immediately afterabdominal surgery because of the normal ileus following the procedure);antidepressants (e.g., in situations where compliance is an issue as inAlzheimer's disease or when maintaining stable blood levels results in asignificant reduction of anti-cholinergic side effects and bettertolerance by patients), such as amitriptylin, imipramin, prozac, etc.;antihypertensive drugs (e.g., to improve compliance and reduce sideeffects associated with fluctuating blood levels), such as diuretics andbeta-blockers (which can be administered by the same patch; e.g.,furosemide and propanolol); antipsychotics (e.g., to facilitatecompliance and make it easier for care giver and family members to makesure that the drug is received), such as haloperidol and chlorpromazine;and anxiolytics or sedatives (e.g., to avoid the reduction of alertnessrelated to high blood levels after oral administration and allow acontinual benefit throughout the day by maintaining therapeutic levelsconstant).

[0202] Numerous other drugs may be administered as described herein,including naturally occurring and synthetic hormones, growth factors,proteins and peptides. For example, insulin and human growth hormone,growth factors like erythropoietin, interleukins and inteferons may bedelivered via the skin.

[0203] Kits for administering a drug via the skin of a mammal are alsoprovided within the present invention. Such kits generally comprise adevice for transdermal application (e.g., a skin patch) in combinationwith, or impregnated with, one or more modulating agents. A drug mayadditionally be included within such kits.

[0204] Within a related aspect, modulating agents as described hereinmay be used to increase the permeability of endothelial and epithelialcell layers, thereby facilitating sampling of the blood compartment bypassive diffusion. Such methods permit the detection and/or measurementof the levels of specific molecules circulating in the blood. Ingeneral, to sample the blood compartment, it is necessary to perturbadhesion between the epithelial cells (keratinocytes) and theendothelial cells of the microvasculature. Using currently availabletechniques, only small, uncharged molecules may be detected across skinin vivo. The methods described herein are not subject to the same degreeof limitation. Accordingly, a wide variety of blood components may besampled across epithelial and endothelial cell layers. Such sampling maybe achieved across any such cell layers, including skin and gums.

[0205] For example, application of one or more modulating agents to theskin, via a skin patch as described herein, permits the patch tofunction like a sponge to accumulate a small quantity of fluidcontaining a representative sample of the serum. The patch is thenremoved after a specified amount of time and analyzed by suitabletechniques for the compound of interest (e.g., a medication, hormone,growth factor, metabolite or marker). Alternatively, a patch may beimpregnated with reagents to permit a color change if a specificsubstance (e.g., an enzyme) is detected. Substances that can be detectedin this manner include, but are not limited to, illegal drugs such ascocaine, HIV enzymes, glucose and PSA. This technology is of particularbenefit for home testing kits.

[0206] To facilitate sampling of blood in a patient, a modulating agentas described above for enhancing drug delivery is contacted with theskin surface. Modulating agent(s) and reagents for assaying bloodcomponents may, but need not, be contained within the same compositionor skin patch. In general, the amount of modulating agent administeredvia the skin may vary as described above. Such levels may be achieved byappropriate adjustments to the device used, or by applying a creamformulated as described above. Transfer of the blood component acrossthe skin may be predicted based on in vitro studies using, for example,a Franz cell apparatus, and evaluated in vivo by appropriate means thatwill be apparent to those of ordinary skill in the art.

[0207] Kits for sampling blood component via, for example, the skin orgums of a mammal, are also provided within the present invention. Suchkits generally comprise a device for transdermal application (i.e., skinpatch) in combination with, or impregnated with, one or more modulatingagents. A reagent for detection of a blood component may additionally beincluded within such kits.

[0208] Within a further aspect, methods are provided for enhancingdelivery of a drug to a tumor in a mammal, comprising administering amodulating agent in combination with a drug to a tumor-bearing mammal.Modulating agents for use within such methods include those designed todisrupt functions mediated by OB-cadherin, cadherin-5, cadherin-6, adesmoglein and/or a desmocollin, and may further disrupt E-cadherinand/or N-cadherin mediated cell adhesion. For example, such a modulatingagent may comprise a CAR sequence (or analogue or mimetic thereof)derived from one or more of the above cadherins, as described above. Amodulating agent may further comprise an E- and/or N-cadherin CARsequence (e.g., HAV, SHAVSS (SEQ ID NO:59), AHAVDI (SEQ ID NO:60) or aanalogue of such a sequence). Bi-functional modulating agents thatcomprise the nonclassical cadherin CAR sequence with either flankingE-cadherin-specific sequences or flanking N-cadherin-specific sequencesjoined via a linker to the nonclassical cadherin CAR sequence are alsopreferred. Preferably, the peptide portion(s) of a modulating agentcomprises 6-16 amino acids, since longer peptides are difficult todissolve in aqueous solution and are more likely to be degraded bypeptidases.

[0209] In one particularly preferred embodiment, a modulating agent iscapable of disrupting cell adhesion mediated by multiple adhesionmolecules. For example, a single branched modulating agent (or multipleagents linked to a single molecule or support material) may disruptadhesion mediated by a nonclassical cadherin, as well as E-cadherin,N-cadherin, occludin, claudin and integrin mediated cell adhesion. Suchagents serve as multifunctional disrupters of cell adhesion.Alternatively, a separate modulator may be administered in conjunctionwith the modulating agent(s), either within the same pharmaceuticalcomposition or separately. Preferred antibody modulating agents includeFab fragments directed against a nonclassical or classical cadherin CARsequence, as described above. A Fab fragment may be incorporated into amodulating agent or may be present within a separate modulator that isadministered concurrently.

[0210] Preferably, the modulating agent and the drug are formulatedwithin the same composition or drug delivery device prior toadministration. In general, a modulating agent may enhance drug deliveryto any tumor (e.g., breast tumor, stomach tumor, ovarian tumor or kidneytumor), and the method of administration may be chosen based on the typeof target tumor. For example, injection or topical administration asdescribed above may be preferred for melanomas and other accessibletumors (e.g., metastases from primary ovarian tumors may be treated byflushing the peritoneal cavity with the composition). Other tumors(e.g., breast tumors) may be treated by injection of the modulatingagent and the drug (such as mitomycin C) into the site of the tumor. Inother instances, the composition may be administered systemically, andtargeted to the tumor using any of a variety of specific targetingagents. Suitable drugs may be identified by those of ordinary skill inthe art based upon the type of cancer to be treated (e.g., taxol forbreast cancer). In general, the amount of modulating agent administeredvaries with the method of administration and the nature of the tumor,within the typical ranges provided above, preferably ranging from about1 μg/mL to about 2 mg/mL, and more preferably from about 10 μg/mL to 1mg/mL. Transfer of the drug to the target tumor may be evaluated byappropriate means that will be apparent to those of ordinary skill inthe art. Drugs may also be labeled (e.g., using radionuclides) to permitdirect observation of transfer to the target tumor using standardimaging techniques.

[0211] Within a related aspect, the present invention provides methodsfor treating cancer and/or inhibiting metastasis in a mammal. Modulatingagents for use within such methods include those designed to disruptfunctions mediated by OB-cadherin, cadherin-5, cadherin-6, a desmogleinand/or a desmocollin, and may further disrupt E-cadherin, N-cadherinand/or integrin mediated cell adhesion. For example, such a modulatingagent may comprise a CAR sequence (or analogue or mimetic thereof)derived from one or more of the above cadherins, as described above,optionally in combination with a sequence such as HAV, SHAVSS (SEQ IDNO:59), AHAVDI (SEQ ID NO:68), RGD, YIGSR (SEQ ID NO:48) or a derivativeof such a sequence. Preferably, the peptide portion(s) of suchmodulating agents comprise 6-16 amino acids. Preferred antibodymodulating agents include Fab fragments directed against a nonclassicalor classical cadherin CAR sequence. The Fab fragments may be eitherincorporated into a modulating agent or may be present within a separatemodulator that is administered concurrently.

[0212] A modulating agent may be administered alone (e.g., via the skin)or within a pharmaceutical composition. For melanomas and certain otheraccessible tumors, injection or topical administration as describedabove may be preferred. For ovarian cancers, flushing the peritonealcavity with a composition comprising one or more modulating agents mayprevent metastasis of ovarian tumor cells. Other tumors (e.g., bladdertumors, bronchial tumors or tracheal tumors) may be treated by injectionof the modulating agent into the cavity. In other instances, thecomposition may be administered systemically, and targeted to the tumorusing any of a variety of specific targeting agents, as described above.Preferably, the tumor is a breast tumor, stomach tumor or kidney tumor.In general, the amount of modulating agent administered varies dependingupon the method of administration and the nature of the cancer, but mayvary within the ranges identified above. The effectiveness of the cancertreatment or inhibition of metastasis may be evaluated using well knownclinical observations, such as monitoring the level of serum tumormarkers (e.g., CEA or PSA).

[0213] The addition of a targeting agent as described above may bebeneficial, particularly when the administration is systemic. Suitablemodes of administration and dosages depend upon the condition to beprevented or treated but, in general, administration by injection isappropriate. Dosages may vary as described above. The effectiveness ofthe inhibition may be evaluated grossly by assessing the inability ofthe tumors to maintain their growth and microscopically by observing anabsence of nerves at the periphery of the tumor.

[0214] Within further aspects, the present invention provides methodsfor inhibiting angiogenesis (i.e., the growth of blood vessels frompre-existing blood vessels) in a mammal. Inhibition of angiogenesis maybe beneficial, for example, in patients afflicted with diseases such ascancer or arthritis. Preferred modulating agents for inhibition ofangiogenesis include those that modulate functions mediated bycadherin-5, such as those that comprises a cadherin-5 CAR sequence oranalogue or mimetic thereof. In addition, a modulating agent for use ininhibiting angiogenesis may comprise the sequence RGD, which isrecognized by integrins, an OB-cadherin CAR sequence.(e.g., DKK), theclassical cadherin CAR sequence HAV, and/or the occludin CAR sequenceLYHY (SEQ ID NO:52), separated from the cadherin-5 sequence via alinker. Alternatively, a separate modulator of classical cadherin-,integrin- or occludin-mediated cell adhesion may be administered inconjunction with the modulating agent(s), either within the samepharmaceutical composition or separately. The ability of a modulatingagent to inhibit angiogenesis may be evaluated as described above.

[0215] The addition of a targeting agent as described above may bebeneficial, particularly when the administration is systemic. Suitablemodes of administration and dosages depend upon the condition to beprevented or treated but, in general, administration by injection isappropriate. Dosages may vary as described above. The effectiveness ofthe inhibition may be evaluated grossly by assessing the inability ofthe tumors to maintain their growth and microscopically by observing anabsence of nerves at the periphery of the tumor.

[0216] In yet another related aspect, the present invention providesmethods for inducing apoptosis in a nonclassical cadherin-expressingcell. In general, patients afflicted with cancer may benefit from suchtreatment. Modulating agents for use within such methods may modulatefunctions mediated any nonclassical cadherin(s). Such agents maycomprise, for example, a CAR sequence of such a cadherin, or an analogueor mimetic thereof. In addition, such agents may comprise a sequencesuch as HAV, SHAVSS (SEQ ID NO:59), AHAVDI (SEQ ID NO:60), RGD, YIGSR(SEQ ID NO:48) or an analogue of such a sequence. Preferably, thepeptide portion(s) of such modulating agents comprise 6-16 amino acids.Preferred antibody modulating agents include Fab fragments directedagainst a nonclassical or classical cadherin CAR sequence. The Fabfragments may be either incorporated into a modulating agent or within aseparate modulator that is administered concurrently. Administration maybe topical, via injection or by other means, and the addition of atargeting agent may be beneficial, particularly when the administrationis systemic. Suitable modes of administration and dosages depend uponthe location and nature of the cells for which induction of apoptosis isdesired but, in general, dosages may vary as described above. A biopsymay be performed to evaluate the level of induction of apoptosis.

[0217] Within a related aspect, the present invention provides methodsfor treating obesity in a mammal, by using modulating agents thatdisrupt OB-cadherin function to inhibit adipocyte adhesion.Alternatively, modulating agents that inhibit angiogenesis as describedherein may be used to inhibit fat cell growth. Modulating agents asdescribed herein may be administered alone, or in combination with otheragents, which may comprise, for example, a cadherin-5 CAR sequence, HAV,SHAVSS (SEQ ID NO:59), AHAVDI (SEQ ID NO:60), RGD or an analogue of sucha sequence. Preferably the peptide portion(s) of such modulating agentscomprise 6-16 amino acids. The use of Fab fragments directed against anOB-cadherin, cadherin-5 or N-cadherin CAR sequence is also preferred. Amodulating agent may be administered alone (e.g., via the skin) orwithin a pharmaceutical composition. Injection or topical administrationas described above may be preferred. In other instances, the compositionmay be administered systemically.

[0218] In another embodiment, methods are provided for causing theregression of blood vessels for the treatment of conditions such ascancer, psoriasis, arthritis, and age-related macular degeneration.Cancer tumors are solid masses of cells, growing out of control, whichrequire nourishment via blood vessels. The formation of new capillariesis a prerequisite for tumor growth and the emergence of metastases.Administration of the modulating agents described herein may disruptblood vessels and cause them to regress, thereby providing effectivetherapy for patients afflicted with diseases such as cancer. Certainpreferred modulating agents for use within such methods comprise, inaddition to a nonclassical cadherin CAR sequence (preferably anOB-cadherin or cadherin-5 CAR sequence), a sequence such as HAV and RGD,or an analogue of such a sequence. Preferably, the peptide portion(s) ofsuch modulating agents comprise 6-16 amino acids. Preferred antibodymodulating agents include Fab fragments directed against thenonclassical cadherin CAR sequence, with or without Fab fragmentsdirected against one or more classical cadherin CAR sequences. The Fabfragments may be either incorporated into a modulating agent or within aseparate modulator that is administered concurrently. Administration maybe topical, via injection or by other means, and the addition of atargeting agent may be beneficial, particularly when the administrationis systemic. Suitable modes of administration and dosages depend uponthe location and nature of the pericytes for which disruption of celladhesion is desired but, in general, dosages may vary as describedabove. The effectiveness of the cancer treatment or inhibition ofmetastasis may be evaluated using well known clinical observations suchas the level of serum markers (e.g., CEA or PSA). The addition of atargeting agent may be beneficial, particularly when the administrationis systemic. Suitable modes of administration and dosages depend uponthe condition to be prevented or treated but, in general, administrationby injection is appropriate. Dosages may vary as described above. Theeffectiveness of the inhibition may be evaluated grossly by assessingthe inability of the tumor to maintain growth and microscopically by anabsence of nerves at the periphery of the tumor.

[0219] Within another aspect, the present invention provides methods forenhancing drug delivery to the central nervous system (CNS) of a mammal.The blood/brain barrier is largely impermeable to most neuroactiveagents, and delivery of drugs to the brain of a mammal often requiresinvasive procedures. Using a modulating agent as described herein,however, delivery may be by, for example, systemic administration of amodulating agent-drug-targeting agent combination, injection of amodulating agent (alone or in combination with a drug and/or targetingagent) into the carotid artery or application of a skin patch comprisinga modulating agent to the head of the patient. Modulating agents forenhancing drug delivery to the central nervous system include thoseagents that disrupt functions mediated by OB-cadherin or cadherin-5.Certain preferred modulating agents for use within such methods arerelatively small cyclic peptides (e.g., a ring size of 4-10 residues;preferably 5-7 residues). Also preferred are multi-functional modulatingagents comprising a nonclassical cadherin CAR sequence and an N-cadherinCAR sequence, the putative claudin CAR sequence IYSY (SEQ ID NO:51)and/or occludin CAR sequence, preferably joined by a linker.Alternatively, a separate modulator of N-cadherin, claudin and/oroccludin-mediated cell adhesion may be administered in conjunction withthe modulating agent(s), either within the same pharmaceuticalcomposition or separately. Modulating agents may further compriseantibodies or Fab fragments directed against the N-cadherin CAR sequenceFHLRAHAVDINGNQV-NH₂ (SEQ ID NO:61). Fab fragments directed against theoccludin CAR sequence GVNPTAQSSGSLYGSQIYALCNQFYTPAATGLYVDQYLYHYCVVDPQE(SEQ ID NO:62) may also be employed, either incorporated into themodulating agent or administered concurrently as a separate modulator.In general, the amount of modulating agent administered varies with themethod of administration and the nature of the condition to be treatedor prevented, but typically varies as described above. Transfer of thedrug to the central nervous system may be evaluated by appropriate meansthat will be apparent to those of ordinary skill in the art, such asmagnetic resonance imaging (MRI) or PET scan (positron emittedtomography).

[0220] The present invention also provides, within further aspects,methods for enhancing and/or directing neurological growth. In one suchaspect, neurite outgrowth may be enhanced and/or directed by contactinga neuron with one or more modulating agents. Modulating agents forenhancing and/or directing neurological growth include those agents thatdisrupt functions mediated by one or more of cadherin-7, cadherin-8,cadherin-12, cadherin-14, cadherin-15, T-cadherin, PB cadherin, aprotocadherin and/or a cadherin-related neuronal receptor. Preferredmodulating agents for use within such methods are linked to a polymericmatrix or other support and/or contain multiple CAR sequences separatedby one or more linkers. In addition, a modulating agent comprising thecadherin CAR sequence HAV, RGD and/or YIGSR (SEQ ID NO:48), which arebound by integrins, and/or the N-CAM CAR sequence KYSFNYDGSE (SEQ IDNO:63) may further facilitate neurite outgrowth. Modulating agentscomprising antibodies, or fragments thereof, may be used within thisaspect of the present invention without the use of linkers or supportmaterials. In addition, Fab fragments directed against the N-CAM CARsequence KYSFNYDGSE (SEQ ID NO:63) or the N-cadherin CAR sequenceFHLRAHAVDINGNQV-NH₂ (SEQ ID NO:61) may be employed, either incorporatedinto the modulating agent or administered concurrently as a separatemodulator.

[0221] The method of achieving contact and the amount of modulatingagent used will depend upon the location of the neuron and the extentand nature of the outgrowth desired. For example, a neuron may becontacted (e.g., via implantation) with modulating agent(s) linked to asupport material such as a suture, fiber nerve guide or other prostheticdevice such that the neurite outgrowth is directed along the supportmaterial. Alternatively, a tubular nerve guide may be employed, in whichthe lumen of the nerve guide contains a composition comprising themodulating agent(s). In vivo, such nerve guides or other supportedmodulating agents may be implanted using well known techniques to, forexample, facilitate the growth of severed neuronal connections and/or totreat spinal cord injuries. It will be apparent to those of ordinaryskill in the art that the structure and composition of the supportshould be appropriate for the particular injury being treated. In vitro,a polymeric matrix may similarly be used to direct the growth of neuronsonto patterned surfaces as described, for example, in U.S. Pat. No.5,510,628.

[0222] Within another aspect, one or more modulating agents may be usedfor therapy of a demyelinating neurological disease in a mammal. Thereare a number of demyelinating diseases, such as multiple sclerosis,characterized by oligodendrocyte death. Modulating agents for treatingand/or preventing such diseases include those agents that disruptfunctions mediated by one or more of cadherin-7, cadherin-8,cadherin-12, cadherin-14, cadherin-15, T-cadherin, PB cadherin, aprotocadherin and/or a cnr. Modulating agents may further comprise HAV,RGD and/or YIGSR (SEQ ID NO:48), which are bound by integrins, and/orthe N-CAM CAR sequence KYSFNYDGSE (SEQ ID NO:63). Such agents, whenimplanted with Schwann cells into the central nervous system, mayfacilitate Schwann cell migration and permit the practice of Schwanncell replacement therapy.

[0223] Multiple sclerosis patients suitable for treatment may beidentified by criteria that establish a diagnosis of clinically definiteor clinically probable MS (see Poser et al., Ann. Neurol. 13:227, 1983).Candidate patients for preventive therapy may be identified by thepresence of genetic factors, such as HLA-type DR2a and DR2b, or by thepresence of early disease of the relapsing remitting type.

[0224] Schwann cell grafts may be implanted directly into the brainalong with the modulating agent(s) using standard techniques. Suitableamounts of modulating agent generally range as described above,preferably from about 10 μg/mL to about 1 mg/mL. Alternatively, amodulating agent may be implanted with oligodendrocyte progenitor cells(OPs) derived from donors not afflicted with the demyelinating disease.The myelinating cell of the CNS is the oligodendrocyte. Although matureoligodendrocytes and immature cells of the oligodendrocyte lineage, suchas the oligodendrocyte type 2 astrocyte progenitor, have been used fortransplantation, OPs are more widely used. OPs are highly motile and areable to migrate from transplant sites to lesioned areas where theydifferentiate into mature myelin-forming oligodendrocytes and contributeto repair of demyelinated axons (see e.g., Groves et al., Nature362:453-55, 1993; Baron-Van Evercooren et al., Glia 16:147-64, 1996).OPs can be isolated using routine techniques known in the art (see e.g.,Milner and French-Constant, Development 120:3497-3506, 1994), from manyregions of the CNS including brain, cerebellum, spinal cord, optic nerveand olfactory bulb. Substantially greater yields of OP's are obtainedfrom embryonic or neonatal rather than adult tissue. OPs may be isolatedfrom human embryonic spinal cord and cultures of neurospheresestablished. Human fetal tissue is a potential valuable and renewablesource of donor OP's for future, long range transplantation therapies ofdemyelinating diseases such as MS.

[0225] OPs can be expanded in vitro if cultured as “homotypicaggregates” or “spheres” (Avellana-Adalid et al, J. Neurosci. Res.45:558-70, 1996). Spheres (sometimes called “oligospheres” or“neurospheres”) are formed when OPs are grown in suspension in thepresence of growth factors such as PDGF and FGF. OPs can be harvestedfrom spheres by mechanical dissociation and used for subsequenttransplantation or establishment of new spheres in culture.Alternatively, the spheres themselves may be transplanted, providing a“focal reservoir” of OPs (Avellana-Adalid et al, J. Neurosci. Res.45:558-70, 1996). 1 An alternative source of OP may be spheres derivedfrom CNS stem cells. Recently, Reynolds and Weiss, Dev. Biol. 165:1-13,1996 have described spheres formed from EGF-responsive cells derivedfrom embryonic neuroepithelium, which appear to retain thepluripotentiality exhibited by neuroepithelium in vivo. Cellsdissociated from these spheres are able to differentiate into neurons,oligodendrocytes and astrocytes when plated on adhesive substrates inthe absence of EGF, suggesting that EGF-responsive cells derived fromundifferentiated embryonic neuroepithelium may represent CNS stem cells(Reynolds and Weiss, Dev. Biol. 165:1-13, 1996). Spheres derived fromCNS stem cells provide an alternative source of OP which may bemanipulated in vitro for transplantation in vivo. Spheres composed ofCNS stem cells may further provide a microenvironment conducive toincreased survival, migration, and differentiation of the OPs in vivo.

[0226] The use of neurospheres for the treatment of MS may befacilitated by modulating agents that enhance cell migration from thespheres. In the absence of modulating agent, the cells within thespheres adhere tightly to one another and migration out of the spheresis hindered. Modulating agents that disrupt N-cadherin mediated celladhesion as described herein, when injected with neurospheres into thecentral nervous system, may improve cell migration and increase theefficacy of OP replacement therapy. Neurosphere grafts may be implanteddirectly into the central nervous system along with the modulatingagent(s) using standard techniques.

[0227] Alternatively, a modulating agent may be administered alone orwithin a pharmaceutical composition. The duration and frequency ofadministration will be determined by such factors as the condition ofthe patient, and the type and severity of the patient's disease. Withinparticularly preferred embodiments of the invention, the modulatingagent or pharmaceutical composition may be administered at a dosageranging from 0.1 mg/kg to 20 mg/kg although appropriate dosages may bedetermined by clinical trials. Methods of administration includeinjection, intravenous or intrathecal (i.e., directly in cerebrospinalfluid). A modulating agent or pharmaceutical composition may furthercomprise a drug (e.g., an immunomodulatory drug).

[0228] Effective treatment of multiple sclerosis may be evidenced by anyof the following criteria: EDSS (extended disability status scale),appearance of exacerbations or MRI (magnetic resonance imaging). TheEDSS is a means to grade clinical impairment due to MS (Kurtzke,Neurology 33:1444, 1983), and a decrease of one full step defines aneffective treatment in the context of the present invention (Kurtzke,Ann. Neurol. 36:573-79, 1994). Exacerbations are defined as theappearance of a new symptom that is attributable to MS and accompaniedby an appropriate new neurologic abnormality (Sipe et al., Neurology34:1368, 1984). Therapy is deemed to be effective if there is astatistically significant difference in the rate or proportion ofexacerbation-free patients between the treated group and the placebogroup or a statistically significant difference in the time to firstexacerbation or duration and severity in the treated group compared tocontrol group. MRI can be used to measure active lesions usinggadolinium-DTPA-enhanced imaging (McDonald et al. Ann. Neurol. 36:14,1994) or the location and extent of lesions using T₂-weightedtechniques. The presence, location and extent of MS lesions may bedetermined by radiologists using standard techniques. Improvement due totherapy is established when there is a statistically significantimprovement in an individual patient compared to baseline or in atreated group versus a placebo group.

[0229] Efficacy of the modulating agent in the context of prevention maybe judged based on clinical measurements such as the relapse rate andEDSS. Other criteria include a change in area and volume of T2 images onMRI, and the number and volume of lesions determined by gadoliniumenhanced images.

[0230] The present invention also provides methods for increasingvasopermeability in a mammal by administering one or more modulatingagents or pharmaceutical compositions. Modulating agents as describedherein that decrease OB-cadherin and/or cadherin-5 mediate cell adhesionmay be used to increase vascular permeability. Certain preferredmodulating agents for use within such methods further inhibitN-cadherin, claudin and/or occludin mediated adhesion. Such agents maycomprise, in addition to an OB-cadherin and/or cadherin-5 CAR sequence,a sequence such as LYHY (the occludin CAR sequence; SEQ ID NO:52), IYSY(the putative claudin CAR sequence; SEQ ID NO:51) HAV and RGD, or ananalogue of such a sequence. Preferably, the peptide portion(s) of suchmodulating agents comprise 6-16 amino acids. Preferred antibodymodulating agents include Fab fragments directed against one or more ofthe OB-cadherin, cadherin-5, classical cadherin, claudin and/or occludinCAR sequences. The Fab fragments may be either incorporated into amodulating agent or within a separate modulator that is administeredconcurrently.

[0231] Treatment with a modulating agent may be appropriate, forexample, prior to administration of an anti-tumor therapeutic ordiagnostic agent (e.g., a monoclonal antibody or other macromolecule),an antimicrobial agent or an anti-inflammatory agent, in order toincrease the concentration of such agents in the vicinity of the targettumor, organism or inflammation without increasing the overall dose tothe patient. Modulating agents for use within such methods may be linkedto a targeting agent to further increase the local concentration ofmodulating agent, although systemic administration of a vasoactive agenteven in the absence of a targeting agent increases the perfusion ofcertain tumors relative to other tissues. Suitable targeting agentsinclude antibodies and other molecules that specifically bind to tumorcells or to components of structurally abnormal blood vessels. Forexample, a targeting agent may be an antibody that binds to a fibrindegradation product or a cell enzyme such as a peroxidase that isreleased by granulocytes or other cells in necrotic or inflamed tissues.

[0232] Administration via intravenous injection or transdermaladministration is generally preferred. Effective dosages are generallysufficient to increase localization of a subsequently administereddiagnostic or therapeutic agent to an extent that improves the clinicalefficacy of therapy of accuracy of diagnosis to a statisticallysignificant degree. Comparison may be made between treated and untreatedtumor host animals to whom equivalent doses of the diagnostic ortherapeutic agent are administered. In general, dosages range asdescribed above.

[0233] In certain other aspects, the present invention provides methodsfor enhancing adhesion of nonclassical cadherin-expressing cells. Withincertain embodiments, a modulating agent may be linked to a solidsupport, resulting in a matrix that comprises multiple modulatingagents. Within one such embodiment, the support is a polymeric matrix towhich modulating agents and molecules comprising other CAR sequence(s)are attached (e.g., modulating agents and molecules comprising eitherHAV or RGD sequences may be attached to the same matrix, preferably inan alternating pattern). Such matrices may be used in contexts in whichit is desirable to enhance adhesion mediated by multiple cell adhesionmolecules. Alternatively, the modulating agent itself may comprisemultiple nonclassical cadherin CAR sequences or antibodies (or fragmentsthereof, separated by linkers as described above. Either way, themodulating agent(s) function as a “biological glue” to bind multiplenonclassical cadherin-expressing cells within a variety of contexts.

[0234] Within one such aspect, modulating agents comprising thenonclassical cadherin CAR sequence and/or multiple modulating agentslinked to a single molecule or support material may be used tofacilitate wound healing and/or reduce scar tissue in a mammal. Peptidesthat may be linked to a support, and/or to one another via a linker, togenerate a suitable modulating agent include, but are not limited to,one or more nonclassical cadherin CAR sequences, or analogues ormimetics thereof. Suitable nonclassical CAR sequences includeOB-cadherin, cadherin-5, desmoglein and/or desmocollin CAR sequences.Such nonclassical CAR sequences may be used in combination with one ormore classical cadherin CAR sequences, including HAV, SHAVSS (SEQ IDNO:59), AHAVDI (SEQ ID NO:60), or an analogue of such a sequence.Preferred antibody modulating agents include Fab fragments directedagainst either the nonclassical cadherin or E-cadherin CAR sequences.Modulating agents that are linked to a biocompatible and biodegradablematrix such as cellulose or collagen are particularly preferred. For usewithin such methods, a modulating agent should have a free amino orhydroxyl group. The modulating agents are generally administeredtopically to the wound, where they may facilitate closure of the woundand may augment, or even replace, stitches. Similarly, administration ofmatrix-linked modulating agents may facilitate cell adhesion in skingrafting and prosthetic implants, and may prolong the duration andusefulness of collagen injection. In general, the amount ofmatrix-linked modulating agent administered to a wound, graft or implantsite varies with the severity of the wound and/or the nature of thewound, graft, or implant, but may vary as discussed above.Multi-functional modulating agents comprising a nonclassical cadherinsequence, a classical cadherin CAR sequence (HAV), and the CAR sequencebound by certain integrins (RGD) may also be used as potent stimulatorsof wound healing and/or to reduce scar tissue. Alternatively, one ormore separate modulators of classical cadherin- or integrin-mediatedcell adhesion may be administered in conjunction with the modulatingagent(s), either within the same pharmaceutical composition orseparately.

[0235] Within another aspect, one or more modulating agents may belinked to the interior surface of a tissue culture plate or other cellculture support, such as for use in a bioreactor. Such linkage may beperformed by any suitable technique, as described above. Modulatingagents linked in this fashion may generally be used to immobilizecadherin-expressing cells. For example, dishes or plates coated with oneor more modulating agents may be used to immobilize cadherin-expressingcells within a variety of assays and screens. Within bioreactors (i.e.,systems for large scale production of cells or organoids), modulatingagents may generally be used to improve cell attachment and stabilizecell growth. Modulating agents may also be used within bioreactors tosupport the formation and function of highly differentiated organoidsderived, for example, from dispersed populations of fetal mammaliancells. Bioreactors containing biomatrices of modulating agent(s) mayalso be used to facilitate the production of specific proteins.

[0236] Modulating agents as described herein may be used within avariety of bioreactor configurations. In general, a bioreactor isdesigned with an interior surface area sufficient to support largenumbers of adherent cells. This surface area can be provided usingmembranes, tubes, microtiter wells, columns, hollow fibers, rollerbottles, plates, dishes, beads or a combination thereof. A bioreactormay be compartmentalized. The support material within a bioreactor maybe any suitable material known in the art; preferably, the supportmaterial does not dissolve or swell in water. Preferred supportmaterials include, but are not limited to, synthetic polymers such asacrylics, vinyls, polyethylene, polypropylene, polytetrafluoroethylene,nylons, polyurethanes, polyamides, polysulfones and poly(ethyleneterephthalate); ceramics; glass and silica.

[0237] Within a further aspect, modulating agents as described hereinmay be used for controlled inhibition of synaptic stability, resultingin increased synaptic plasticity. Within this aspect, administration ofone or more modulating agents that inhibit cnr-mediated cell adhesionmay be advantageous for repair processes within the brain, as well aslearning and memory, in which neural plasticity is a key early event inthe remodeling of synapses. In addition, a preferred modulating agentmay comprise one or more additional CAR sequences, such as HAV, RGDand/or the N-CAM CAR sequence KYSFNYDGSE (SEQ ID NO:63). As noted above,such additional sequence(s) may be separated from the nonclassical CARsequence via a linker. Alternatively, a separate modulator of celladhesion mediated by a different adhesion molecule may be administeredin conjunction with the modulating agent(s), either within the samepharmaceutical composition or separately. For such aspects,administration may be via encapsulation into a delivery vehicle such asa liposome, using standard techniques, and injection into, for example,the carotid artery. Alternatively, a modulating agent may be linked to adisrupter of the blood-brain barrier. In general dosages range asdescribed above.

[0238] Within further aspects, modulating agents as described herein maybe used for modulating the immune system of a mammal in any of severalways. Cadherins are expressed on immature B and T cells (thymocytes andbone marrow pre-B cells), as well as on specific subsets of activated Band T lymphocytes and some hematological malignancies. Modulating agentsmay generally be used to modulate specific steps within cellularinteractions during an immune response or during the dissemination ofmalignant lymphocytes.

[0239] For example, a modulating agent as described herein may be usedto treat diseases associated with excessive generation of otherwisenormal T cells. Without wishing to be bound by any particular theory, itis believed that the interaction of cadherins on maturing T cells and Bcell subsets contributes to protection of these cells from programmedcell death. A modulating agent may decrease such interactions, leadingto the induction of programmed cell death. Accordingly, modulatingagents may be used to treat certain types of diabetes and rheumatoidarthritis, particularly in young children where the cadherin expressionon thymic pre-T cells is greatest.

[0240] Modulating agents may also be administered to patients afflictedwith certain skin disorders (such as cutaneous lymphomas), acute B cellleukemia and excessive immune reactions involving the humoral immunesystem and generation of immunoglobulins, such as allergic responses andantibody-mediated graft rejection. In addition, patients withcirculating cadherin-positive malignant cells (e.g., during regimeswhere chemotherapy or radiation therapy is eliminating a major portionof the malignant cells in bone marrow and other lymphoid tissue) maybenefit from treatment with a modulating agent. Such treatment may alsobenefit patients undergoing transplantation with peripheral blood stemcells.

[0241] Preferred modulating agents for use within such methods includethose that disrupt OB-cadherin, cadherin-5, cadherin-6 and/or cadherin-8mediated cell adhesion. In addition, a preferred modulating agent maycomprise one or more additional CAR sequences, such as HAV, RGD, LYHY(SEQ ID NO:52) and/or KYSFNYDGSE (SEQ ID NO:63). As noted above, suchadditional sequence(s) may be separated from a nonclassical CAR sequencevia a linker. Alternatively, a separate modulator of classicalcadherin-, occludin-, integrin- and/or N-CAM-mediated cell adhesion maybe administered in conjunction with the modulating agent(s), eitherwithin the same pharmaceutical composition or separately.

[0242] Within the above methods, the modulating agent(s) are preferablyadministered systemically (usually by injection) or topically. Amodulating agent may be linked to a targeting agent. For example,targeting to the bone marrow may be beneficial. A suitable dosage issufficient to effect a statistically significant reduction in thepopulation of B and/or T cells that express cadherin and/or animprovement in the clinical manifestation of the disease being treated.Typical dosages generally range as described above.

[0243] Within further aspects, the present invention provides methodsand kits for preventing pregnancy in a mammal. In general, disruption ofOB-cadherin function prevents the adhesion of trophoblasts and theirsubsequent fusion to form syncitiotrophoblasts, whereas disruption ofcadherin-5 function prevents angiogenesis. In one embodiment, one ormore modulating agents may be incorporated into any of a variety of wellknown contraceptive devices, such as sponges suitable for intravaginalinsertion (see, e.g., U.S. Pat. No. 5,417,224) or capsules for subdermalimplantation. Other modes of administration are possible, however,including transdermal administration, for modulating agents linked to anappropriate targeting agent. Preferred modulating agents for use withinsuch methods include those comprising an OB-cadherin and/or cadherin-5CAR sequence, or analogue or mimetic thereof. In addition, a preferredmodulating agent may comprise additional CAR sequences, such as HAVand/or RGD. As noted above, such additional sequences may be separatedfrom the nonclassical CAR sequence via a linker. Alternatively, aseparate modulator of classical cadherin- and/or integrin-mediated celladhesion may be administered in conjunction with the modulatingagent(s), either within the same pharmaceutical composition orseparately.

[0244] Suitable methods for incorporation into a contraceptive devicedepend upon the type of device and are well known in the art. Suchdevices facilitate administration of the modulating agent(s) to theuterine region and may provide a sustained release of the modulatingagent(s). In general, modulating agent(s) may be administered via such acontraceptive device at a dosage ranging from 0.1 to 50 mg/kg, althoughappropriate dosages may be determined by monitoring hCG levels in theurine. hCG is produced by the placenta, and levels of this hormone risein the urine of pregnant women. The urine hCG levels can be assessed byradio-immunoassay using well known techniques. Kits for preventingpregnancy generally comprise a contraceptive device impregnated with oneor more modulating agents.

[0245] Alternatively, a sustained release formulation of one or moremodulating agents may be implanted, typically subdermally, in a mammalfor the prevention of pregnancy. Such implantation may be performedusing well known techniques. Preferably, the implanted formulationprovides a dosage as described above, although the minimum effectivedosage may be determined by those of ordinary skill in the art using,for example, an evaluation of hCG levels in the urine of women.

[0246] Other aspects of the present invention provide methods thatemploy antibodies raised against the nonclassical CAR sequences fordiagnostic and assay purposes. Assays typically involve using anantibody to detect the presence or absence of a nonclassical cadherin(free or on the surface of a cell), or proteolytic fragments containingone or more EC domains in a suitable biological sample, such as tumor ornormal tissue biopsies, blood, lymph node, serum or urine samples, orother tissue, homogenate, or extract thereof obtained from a patient.

[0247] There are a variety of assay formats known to those of ordinaryskill in the art for using an antibody to detect a target molecule in asample. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual,Cold Spring Harbor Laboratory, 1988. For example, the assay may beperformed in a Western blot format, wherein a protein preparation fromthe biological sample is submitted to gel electrophoresis, transferredto a suitable membrane and allowed to react with the antibody. Thepresence of the antibody on the membrane may then be detected using asuitable detection reagent, as described below.

[0248] In another embodiment, the assay involves the use of antibodyimmobilized on a solid support to bind to the target cadherin, or aproteolytic fragment containing an extracellular domain and encompassinga CAR sequence, and remove it from the remainder of the sample. Thebound cadherin may then be detected using a second antibody or reagentthat contains a reporter group. Alternatively, a competitive assay maybe utilized, in which a cadherin is labeled with a reporter group andallowed to bind to the immobilized antibody after incubation of theantibody with the sample. The extent to which components of the sampleinhibit the binding of the labeled cadherin to the antibody isindicative of the reactivity of the sample with the immobilizedantibody, and as a result, indicative of the level of the cadherin inthe sample.

[0249] The solid support may be any material known to those of ordinaryskill in the art to which the antibody may be attached, such as a testwell in a microtiter plate, a nitrocellulose filter or another suitablemembrane. Alternatively, the support may be a bead or disc, such asglass, fiberglass, latex or a plastic such as polystyrene orpolyvinylchloride. The antibody may be immobilized on the solid supportusing a variety of techniques known to those in the art, which are amplydescribed in the patent and scientific literature.

[0250] In certain embodiments, the assay for detection of a nonclassicalcadherin in a sample is a two-antibody sandwich assay. This assay may beperformed by first contacting an antibody that has been immobilized on asolid support, commonly the well of a microtiter plate, with thebiological sample, such that the nonclassical cadherin within the sampleis allowed to bind to the immobilized antibody (a 30 minute incubationtime at room temperature is generally sufficient). Unbound sample isthen removed from the immobilized cadherin-antibody complexes and asecond antibody (containing a reporter group such as an enzyme, dye,radionuclide, luminescent group, fluorescent group or biotin) capable ofbinding to a different site on the cadherin is added. The amount ofsecond antibody that remains bound to the solid support is thendetermined using a method appropriate for the specific reporter group.The method employed for detecting the reporter group depends upon thenature of the reporter group. For radioactive groups, scintillationcounting or autoradiographic methods are generally appropriate.Spectroscopic methods may be used to detect dyes, luminescent groups andfluorescent groups. Biotin may be detected using avidin, coupled to adifferent reporter group (commonly a radioactive or fluorescent group oran enzyme). Enzyme reporter groups may generally be detected by theaddition of substrate (generally for a specific period of time),followed by spectroscopic or other analysis of the reaction products.Standards and standard additions may be used to determine the level ofcadherin in a sample, using well known techniques.

[0251] The present invention also provides kits for use in suchimmunoassays. Such kits generally comprise one or more antibodies, asdescribed above. In addition, one or more additional compartments orcontainers of a kit generally enclose elements, such as reagents,buffers and/or wash solutions, to be used in the immunoassay.

[0252] Within further aspects, modulating agents or antibodies (orfragments thereof may be used to facilitate cell identification andsorting in vitro or imaging in vivo, permitting the selection of cellsexpressing the nonclassical cadherin (or different nonclassical cadherinlevels). Preferably, the modulating agent(s) or antibodies for use insuch methods are linked to a detectable marker. Suitable markers arewell known in the art and include radionuclides, luminescent groups,fluorescent groups, enzymes, dyes, constant immunoglobulin domains andbiotin. Within one preferred embodiment, a modulating agent linked to afluorescent marker, such as fluorescein, is contacted with the cells,which are then analyzed by fluorescence activated cell sorting (FACS).

[0253] Antibodies or fragments thereof may also be used within screensof combinatorial or other nonpeptide-based libraries to identify othercompounds capable of modulating nonclassical cadherin-mediated celladhesion. Such screens may generally be performed using an ELISA orother method well known to those of ordinary skill in the art thatdetect compounds with a shape and structure similar to that of themodulating agent. In general, such screens may involve contacting anexpression library producing test compounds with an antibody, anddetecting the level of antibody bound to the candidate compounds.Compounds for which the antibody has a higher affinity may be furthercharacterized as described herein, to evaluate the ability to modulateOB-cadherin-mediated cell adhesion.

[0254] The following examples are offered by way of illustration and notby way of limitation.

EXAMPLES Example 1 Preparation of Representative Modulating Agents

[0255] This Example illustrates the solid phase synthesis ofrepresentative peptide modulating agents.

[0256] The peptides were synthesized on a 431A Applied Biosystemspeptide synthesizer using p-Hydroxymethylphenoxymethyl polystyrene (HMP)resin and standard Fmoc chemistry. After synthesis and deprotection, thepeptides were de-salted on a Sephadex G-10 column and lyophilized. Thepeptides were analyzed for purity by analytical HPLC, and in each case asingle peak was observed. Peptides were made as stock solutions at 10 to25 mg/mL in dimethylsulfoxide (DMSO) or water and stored at −20° C.before use.

Example 2 Disruption of Human Breast Cancer Cell Adhesion

[0257] This Example illustrates the ability of a representative linearpeptide comprising an OB-cadherin CAR sequence to disrupt human breastepithelial cell adhesion.

[0258] MDA-MB-231 human breast cancer cells (Lombardi Cancer ResearchCenter, Washington, D.C.) were used in these experiments. They expresscadherin-11 (also known as OB-cadherin) but not N-cadherin orE-cadherin. The cells were plated (˜50,000 cells) on glass coverslipsand cultured for 24 hours in DMEM containing 5% serum. Peptides(N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85) and H-IFVIDDKSG-OH (SEQ ID NO:85))were dissolved in sterile water (10 mg/ml), and 100 μl of each peptidestock solution was added to 1 ml of DMEM containing 5% serum. Controlcells had 100 μl of water added to the medium. Cells were monitored byphase contrast microscopy. After 24 hours cells were fixed informaldehyde. After 24 hours, neither the peptide H-IFVIDDKSG-OH (SEQ IDNO:85) nor water had an effect on cell morphology (FIG. 5A). The cellstreated with either water or H-IFVIDDKSG-OH (SEQ ID NO:85) remainedflattened and well-attached to the substratum. In contrast, the cellstreated with N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85) rounded up from eachother and were not well-attached to the substratum (FIGS. 5A and 5B;arrows indicate rounded cells). These results demonstrate that thepeptide N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85) interferes with cell adhesion.The amino acid sequence of this peptide is identical to that which isfound in the first extracellular domain of OB-cadherin.

Example 3 Disruption of Endothelial Cell Adhesion Using PeptideModulating Agents with a Cadherin-5 CAR Sequence

[0259] This Example illustrates the ability of a representative linearpeptide comprising a cadherin-5 CAR sequence to disrupt endothelial celladhesion.

[0260] Human umbilical vein endothelial cells were cultured usingstandard procedures (see Ichikawa et al., Amer. J. Physiol. 273(Gastrointest. Liver Physiol. 36):3642-6347, 1997). Cells weremaintained in EGM (Clonetics, San Diego, Calif.) and used at P2 for allexperiments. Endothelial identity was established by Dil-LDL and factorVIII staining.

[0261] The cells were cultured on glass coverslips. Monolayers wereexposed to peptides at a concentration of 75 μg/mL for 60 minutes. Thecells were then fixed with 95% ethanol for 30 minutes at 4° C., followedby acetone for one minute and left to air dry at room temperature.Primary antibody for VE-cadherin (Immunotech, Marseilles, France; 1:250)was added for one hour at 37° C. Coverslips were then washed with 0.1%milk/PBS solution three times for five minutes each. Secondary antibody(1:250), goat anti-rabbit FITC (Zymed, San Francisco, Calif.) wasincubated at 37° C. for one hour. Coverslips were again washed with 0.1%milk/PBS solution three times for five minutes each. Coverslips weremounted with anti-quenching solution (1 mg/mL phenylenediamine (Sigma,St. Louis, Mo.) in 50% glycerol, 50% PBS). All photographs were taken at400×and 1000×with exposure times of 12 seconds.

[0262] The resulting photographs are presented in FIGS. 6A-6F. FIGS. 6Aand 6B are control cells. The cells in FIGS. 6C and 6D were exposed to75 μg/mL of H-VFRVDAETGD-OH (SEQ ID NO:64) and the cells in FIGS. 6E and6F were exposed to 75 μg/mL of the linear peptide modulating agentN-Ac-VFRVDAETGD-NH₂ (SEQ ID NO:64). These results indicate that thelinear peptide modulating agent N-Ac-VFRVDAETGD-NH₂ (SEQ ID NO:64)disrupts endothelial cell adhesion, with an activity that issubstantially greater that that of a similar peptide without the N- andC-terminal functional groups.

[0263] From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

0 SEQUENCE LISTING The patent application contains a lengthy “SequenceListing” section. A copy of the “Sequence Listing” is available inelectronic form from the USPTO web site(http://seqdata.uspto.gov/sequence.html?DocID=20030229199). Anelectronic copy of the “Sequence Listing” will also be available fromthe USPTO upon request and payment of the fee set forth in 37 CFR1.19(b)(3).

What is claimed is:
 1. A modulating agent that: (a) comprises anonclassical cadherin CAR sequence; and (b) contains 3-16 amino acidresidues linked by peptide bonds.
 2. A modulating agent that: (a)comprises at least five consecutive amino acid residues of anonclassical cadherin CAR sequence having the formula:Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; IIe/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine and asparagine; and (b)contains no more than 50 consecutive amino acid residues present withinthe nonclassical cadherin.
 3. A modulating agent that: (a) comprises anonclassical cadherin CAR sequence having the formula:Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; IIe/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine or asparagine; and (b)contains no more than 50 consecutive amino acid residues present withinthe nonclassical cadherin.
 4. A modulating agent that: (a) comprises atleast nine consecutive amino acid residues of a nonclassical cadherin,wherein the nine consecutive amino acids comprise a nonclassicalcadherin CAR sequence having the formula:Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; le/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine and asparagine; and (b)contains no more than 50 consecutive amino acid residues present withinthe nonclassical cadherin.
 5. A modulating agent according to any one ofclaims 2-4, wherein the agent is a peptide ranging in size from 3 to 50amino acid residues.
 6. A modulating agent according to any one ofclaims 1-4, wherein the agent is a peptide ranging in size from 4 to 16amino acid residues.
 7. A modulating agent according to any one ofclaims 1-4, wherein the CAR sequence is present within a cyclic peptide.8. A modulating agent according to claim 7, wherein the cyclic peptidehas the formula:

wherein W is a tripeptide selected from the group consisting of EEY,DDK, EAQ, DAE, NEN, ESE, DSG, DEN, EPK, DAN, EEF, NDV, DET, DPK, DDT,DAN, DKF, DEL, DAD, NNK, DLV, NRD, DPS, NQK, NRN, NKD, EKD, ERD, DPV,DSV, DLY, DSN, DSS, DEK and NEK; wherein X₁, and X₂ are optional, and ifpresent, are independently selected from the group consisting of aminoacid residues and combinations thereof in which the residues are linkedby peptide bonds, and wherein X₁ and X₂ independently range in size from0 to 10 residues, such that the sum of residues contained within X₁ andX₂ ranges from 1 to 12; wherein Y₁ and Y₂ are independently selectedfrom the group consisting of amino acid residues, and wherein a covalentbond is formed between residues Y₁ and Y₂; and wherein Z₁ and Z₂ areoptional, and if present, are independently selected from the groupconsisting of amino acid residues and combinations thereof in which theresidues are linked by peptide bonds.
 9. A polynucleotide encoding amodulating agent according to any one of claims 1-4.
 10. An expressionvector comprising a polynucleotide according to claim
 9. 11. A host celltransformed or transfected with an expression vector according to claim10.
 12. A modulating agent comprising an antibody or antigen-bindingfragment thereof that specifically binds to a nonclassical cadherin CARsequence and modulates a nonclassical cadherin-mediated function,wherein the nonclassical cadherin CAR sequence has the formula:Aaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; IIe/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine and asparagine; and whereinthe modulating agent inhibits or enhances a function mediated by thenonclassical cadherin.
 13. A modulating agent comprising a mimetic of anonclassical cadherin CAR sequence that comprises at least threeconsecutive amino acid residues of a nonclassical cadherin CAR sequencehaving the formulaAaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; IIe/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine and asparagine; wherein themimetic is capable of modulating.a nonclassical cadherin-mediatedfunction.
 14. A modulating agent comprising a mimetic of a nonclassicalcadherin CAR sequence that comprises at least five consecutive aminoacid residues of a nonclassical cadherin CAR sequence having the formulaAaa-Phe-Baa-Ile/Leu/Val-Asp/Asn/Glu-Caa-Daa-Ser/Thr/Asn-Gly (SEQ IDNO:3)

wherein Aaa, Baa, Caa and Daa are independently selected amino acidresidues; IIe/Leu/Val is an amino acid that is selected from the groupconsisting of isoleucine, leucine and valine, Asp/Asn/Glu is an aminoacid that is selected from the group consisting of aspartate, asparagineand glutamate; and Ser/Thr/Asn is an amino acid that is selected fromthe group consisting of serine, threonine and asparagine; wherein themimetic is capable of modulating a nonclassical cadherin-mediatedfunction.
 15. A modulating agent according to any one of claims 1-4,wherein the agent comprises one or more OB-cadherin CAR sequencesselected from the group consisting DDK, IDDK (SEQ ID NO:4051) DDKS (SEQID NO:73), VIDDK (SEQ ID NO:74), IDDKS (SEQ ID NO:75), VIDDKS (SEQ IDNO:76), DDKSG (SEQ ID NO:77), IDDKSG (SEQ ID NO:78), VIDDKSG (SEQ IDNO:79), FVIDDK (SEQ ID NO:80), FVIDDKS (SEQ ID NO:81), FVIDDKSG (SEQ IDNO:82), IFVIDDK (SEQ ID NO:83), IFVIDDKS (SEQ ID NO:84), IFVIDDKSG (SEQID NO:85), EEY, IEEY (SEQ ID NO:86), EEYT (SEQ ID NO:87), VIEEY (SEQ IDNO:88), IEEYT (SEQ ID NO:89), VIEEYT (SEQ ID NO:90), EEYTG (SEQ IDNO:91), IEEYTG (SEQ ID NO:92), VIEEYTG (SEQ ID NO:93), FVIEEY (SEQ IDNO:94), FVIEEYT (SEQ ID NO:95), FVIEEYTG (SEQ ID NO:96), FFVIEEY (SEQ IDNO:97), FFVIEEYT (SEQ ID NO:98), FFVIEEYTG (SEQ ID NO:99), EAQ, VEAQ(SEQ ID NO:100), EAQT (SEQ ID NO:101), SVEAQ (SEQ ID NO:102), VEAQT (SEQID NO:103), SVEAQT (SEQ ID NO:104), EAQTG (SEQ ID NO:105), VEAQTG (SEQID NO:106), SVEAQTG (SEQ ID NO:107), FSVEAQ (SEQ ID NO:108), FSVEAQT(SEQ ID NO:109), FSVEAQTG (SEQ ID NO:110), YFSVEAQ (SEQ ID NO:111),YFSVEAQT (SEQ ID NO:112) and YFSVEAQTG (SEQ ID NO:113).
 16. A modulatingagent according to claim 15, wherein the agent comprises a linearpeptide having the sequence N-Ac-IFVIDDKSG-NH₂ (SEQ ID NO:85),N-Ac-FFVIEEYTG-NH₂ (SEQ ID NO:99) or N-Ac-YFSVEAQTG-NH₂ (SEQ ID NO:113).17. A modulating agent according to claim 15, wherein an OB-cadherin CARsequence is present within a cyclic peptide.
 18. A modulating agentaccording to claim 17, wherein the cyclic peptide comprises a sequenceselected from the group consisting of CDDKC (SEQ ID NO₆₆₉), CIDDKC (SEQID NO:670), CDDKSC (SEQ ID NO:671), CVIDDKC (SEQ ID NO:672), CIDDKSC(SEQ ID NO:673), CVIDDKSC (SEQ ID NO:674), CDDKSGC (SEQ ID NO:675),CIDDKSGC (SEQ ID NO:676), CVIDDKSGC (SEQ ID NO:677), CFVIDDKC (SEQ IDNO:678), CFVIDDKSC (SEQ ID NO:679), CFVIDDKSGC (SEQ ID NO:680),CIFVIDDKC (SEQ ID NO:681), CIFVIDDKSC (SEQ ID NO:682), CIFVIDDKSGC (SEQID NO:683), DDDKK (SEQ ID NO:684), DIDDKK (SEQ ID NO:685), DVIDDKK (SEQID NO:686), DFVIDDKK (SEQ ID NO:687), DIFVIDDKK (SEQ ID NO:688), EDDKK(SEQ ID NO:689), EIDDKK (SEQ ID NO:690), EVIDDKK (SEQ ID NO:691),EFVIDDKK (SEQ ID NO:692), EIFVIDDKK (SEQ ID NO:693), FVIDDK (SEQ IDNO:694), FVIDDKS (SEQ ID NO:695), FVIDDKSG (SEQ ID NO:696), KDDKD (SEQID NO:697), KIDDKD (SEQ ID NO:698), KDDKSD (SEQ ID NO:699), KVIDDKD (SEQID NO:700), KIDDKSD (SEQ ID NO:701), KVIDDKSD (SEQ ID NO:702), KDDKSGD(SEQ ID NO:703), KIDDKSGD (SEQ ID NO:704), KVIDDKSGD (SEQ ID NO:705),KFVIDDKD (SEQ ID NO:706), KFVIDDKSD (SEQ ID NO:707), KFVIDDKSGD (SEQ IDNO:708), KIFVIDDKD (SEQ ID NO:709), KIFVIDDKSD (SEQ ID NO:710),KIFVIDDKSGD (SEQ ID NO:711), VIDDK (SEQ ID NO:712), IDDKS (SEQ IDNO:713), VIDDKS (SEQ ID NO:714), VIDDKSG (SEQ ID NO:715), DDKSG (SEQ IDNO:716), IDDKSG (SEQ ID NO:717), IFVIDDK (SEQ ID NO:718), IFVIDDKS (SEQID NO:719), IFVIDDKSG (SEQ ID NO:720), KDDKE (SEQ ID NO:721), KIDDKE(SEQ ID NO:722), KDDKSE (SEQ ID NO:723), KVIDDKE (SEQ ID NO:724),KIDDKSE (SEQ ID NO:725), KVIDDKSE (SEQ ID NO:726), KDDKSGE (SEQ IDNO:727), KIDDKSGE (SEQ ID NO:728), KVIDDKSGE (SEQ ID NO:729), KFVIDDKE(SEQ ID NO:730), KFVIDDKSE (SEQ ID NO:731), KFVIDDKSGE (SEQ ID NO:732),KIFVIDDKE (SEQ ID NO:733), KIFVIDDKSE (SEQ ID NO:734), KIFVIDDKSGE (SEQID NO:735), CEEYC (SEQ ID NO:736), CIEEYC (SEQ ID NO:737), CEEYTC (SEQID NO:738), CVIEEYC (SEQ ID NO:739), CIEEYTC (SEQ ID NO:740), CVIEEYTC(SEQ ID NO:741), CEEYTGC (SEQ ID NO:742), CIEEYTGC (SEQ ID NO:743),CVIEEYTGC (SEQ ID NO:744), CFVIEEYC (SEQ ID NO:745), CFVIEEYTC (SEQ IDNO:746), CFVIEEYTGC (SEQ ID NO:747), CFFVIEEYC (SEQ ID NO:748),CFFVIEEYTC (SEQ ID NO:749), CFFVIEEYTGC (SEQ ID NO:750), KEEYD (SEQ IDNO:751), KIEEYD (SEQ ID NO:752), KEEYTD (SEQ ID NO:753), KVIEEYD (SEQ IDNO:754), KIEEYTD (SEQ ID NO:755), KVIEEYTD (SEQ ID NO:756), KEEYTGCD(SEQ ID NO:757), KIEEYTGD (SEQ ID NO:758), KVIEEYTGD (SEQ ID NO:759),KFVIEEYD (SEQ ID NO:760), KFVIEEYTD (SEQ ID NO:761), KFVIEEYTGD (SEQ IDNO:762), KFFVIEEYD (SEQ ID NO:763), KFFVIEEYTD (SEQ ID NO:764),KFFVIEEYTGD (SEQ ID NO:765), EEEYK (SEQ ID NO:766), EIEEYK (SEQ IDNO:767), EEEYTK (SEQ ID NO:768), EVIEEYK (SEQ ID NO:769), EIEEYTK (SEQID NO:770), EVIEEYTK (SEQ ID NO:771), EEEYTGK (SEQ ID NO:772), EIEEYTGK(SEQ ID NO:773), EVIEEYTGK (SEQ ID NO:774), EFVIEEYK (SEQ ID NO:775),EFVIEEYTK (SEQ ID NO:776), EFVIEEYTGK (SEQ ID NO:777), EFFVIEEYK (SEQ IDNO:778), EFFVIEEYTK (SEQ ID NO:779), EFFVIEEYTGK (SEQ ID NO:780), DCEEYK(SEQ ID NO:781), DIEEYCK (SEQ ID NO:782), DEEYTK (SEQ ID NO:783),DVIEEYK (SEQ ID NO:784), DIEEYTK (SEQ ID NO:785), DVIEEYTK (SEQ IDNO:786), DEEYTGK (SEQ ID NO:787), DIEEYTGK (SEQ ID NO:788), DVIEEYTGK(SEQ ID NO:789), DFVIEEYK (SEQ ID NO:790), DFVIEEYTK (SEQ ID NO:791),DFVIEEYTGK (SEQ ID NO:792), DFFVIEEYK (SEQ ID NO:793), DFFVIEEYTK (SEQID NO:794), DFFVIEEYTGK (SEQ ID NO:795), KEEYE (SEQ ID NO:796), KIEEYE(SEQ ID NO:797), KEEYTE (SEQ ID NO:798), KVIEEYE (SEQ ID NO:799),KIEEYTE (SEQ ID NO:800), KVIEEYTE (SEQ ID NO:801), KEEYTGE (SEQ IDNO:802), KIEEYTGE (SEQ ID NO:803), KVIEEYTGE (SEQ ID NO:804), KFVIEEYE(SEQ ID NO:805), KFVIEEYTE (SEQ ID NO:806), KFVIEEYTGE (SEQ ID NO:807),KFFVIEEYE (SEQ ID NO:808), KFFVIEEYTE (SEQ ID NO:809), KFFVIEEYTGE (SEQID NO:810), VIEEY (SEQ ID NO:810), IEEYT (SEQ ID NO:812), VIEEYT (SEQ IDNO: 813), EEYTG (SEQ ID NO:814), IEEYTG (SEQ ID NO:815), VIEEYTG (SEQ IDNO:816), FVIEEY (SEQ ID NO:817), FVIEEYT (SEQ ID NO:818), FVIEEYTG (SEQID NO:819), FFVIEEY (SEQ ID NO:820), FFVIEEYT (SEQ ID NO:821), FFVIEEYTG(SEQ ID NO:822), CEAQC (SEQ ID NO:823), CVEAQC (SEQ ID NO:824), CEAQTC(SEQ ID NO:825), CSVEAQC (SEQ ID NO:826), CVEAQTC (SEQ ID NO:827),CSVEAQTC (SEQ ID NO:828), CEAQTGC (SEQ ID NO:829), CVEAQTGC (SEQ IDNO:830), CSVEAQTGC (SEQ ID NO:831), CFSVEAQC (SEQ ID NO:832), CFSVEAQTC(SEQ ID NO:833), CFSVEAQTGC (SEQ ID NO:834), CYFSVEAQC (SEQ ID NO:835),CYFSVEAQTC (SEQ ID NO:836), CYFSVEAQTGC (SEQ ID NO:837), KEAQD (SEQ IDNO:838), KVEAQD (SEQ ID NO:839), KEAQTD (SEQ ID NO:840), KSVEAQD (SEQ IDNO:841), KVEAQTD (SEQ ID NO:842), KSVEAQTD (SEQ ID NO:843), KEAQTGD (SEQID NO:844), KVEAQTGD (SEQ ID NO:845), KSVEAQTGD (SEQ ID NO:846),KFSVEAQD (SEQ ID NO:847), KFSVEAQTD (SEQ ID NO:848), KFSVEAQTGD (SEQ IDNO:849), KYFSVEAQD (SEQ ID NO:850), KYFSVEAQTD (SEQ ID NO:851),KYFSVEAQTGD (SEQ ID NO:852), EEAQK (SEQ ID NO:853), EVEAQK (SEQ IDNO:854), EEAQTK (SEQ ID NO:855), ESVEAQK (SEQ ID NO:856), EVEAQTK (SEQID NO:857), ESVEAQTK (SEQ ID NO:858), EEAQTGK (SEQ ID NO:859), EVEAQTGK(SEQ ID NO:860), ESVEAQTGK (SEQ ID NO:861), EFSVEAQK (SEQ ID NO:862),EFSVEAQTK (SEQ ID NO:863), EFSVEAQTGK (SEQ ID NO:864), EYFSVEAQK (SEQ IDNO:865), EYFSVEAQTK (SEQ ID NO:866), EYFSVEAQTGK (SEQ ID NO:867), DEAQK(SEQ ID NO:868), DVEAQK (SEQ ID NO:869), DEAQTK (SEQ ID NO:870), DSVEAQK(SEQ ID NO:871), DVEAQTK (SEQ ID NO:872), DSVEAQTK (SEQ ID NO:873),DEAQTGK (SEQ ID NO:874), DVEAQTGK (SEQ ID NO:875), DSVEAQTGK (SEQ IDNO:876), DFSVEAQK (SEQ ID NO:877), DFSVEAQTK (SEQ ID NO:878), DFSVEAQTGK(SEQ ID NO:879), DYFSVEAQK (SEQ ID NO:880), DYFSVEAQTK (SEQ ID NO:881),DYFSVEAQTGK (SEQ ID NO:882), KEAQE (SEQ ID NO:883), KVEAQE (SEQ IDNO:884), KEAQTE (SEQ ID NO:885), KSVEAQE (SEQ ID NO:886), KVEAQTE (SEQID NO:887), KSVEAQTE (SEQ ID NO:888), KEAQTGE (SEQ ID NO:889), KVEAQTGE(SEQ ID NO:890), KSVEAQTGE (SEQ ID NO:891), KFSVEAQE (SEQ ID NO:892),KFSVEAQTE (SEQ ID NO:893), KFSVEAQTGE (SEQ ID NO:894), KYFSVEAQE (SEQ IDNO:895), KYFSVEAQTE (SEQ ID NO:896), KYFSVEAQTGE (SEQ ID NO:897), SVEAQ(SEQ ID NO:898), VEAQT (SEQ ID NO:899), SVEAQT (SEQ ID NO:900), EAQTG(SEQ ID NO:901), VEAQTG (SEQ ID NO:902), SVEAQTG (SEQ ID NO:903), FSVEAQ(SEQ ID NO:904), FSVEAQT (SEQ ID NO:905), FSVEAQTG (SEQ ID NO:906),YFSVEAQ (SEQ ID NO:907), YFSVEAQT (SEQ ID NO:908) and YFSVEAQTG (SEQ IDNO:909).
 19. A polynucleotide encoding a modulating agent according toclaim
 15. 20. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to anOB-cadherin CAR sequence selected from the group consisting of IFVIDDKSG(SEQ ID NO:85), FFVIEEYTG (SEQ ID NO:99) and YFSVEAQTG (SEQ ID NO: 113)and (b) modulates an OB-cadherin-mediated function.
 21. A modulatingagent according to any one of claims 1-4, wherein the agent comprisesone or more cadherin-5 CAR sequences selected from the group consistingof DAE, VDAE (SEQ ID NO:114), DAET (SEQ ID NO:115), RVDAE (SEQ IDNO:116), VDAET (SEQ ID NO:117), RVDAET (SEQ ID NO:118), DAETG (SEQ IDNO:119), VDAETG (SEQ ID NO:120), RVDAETG (SEQ ID NO:121), FRVDAE (SEQ IDNO:122), FRVDAET (SEQ ID NO:123), FRVDAETG (SEQ ID NO:124), VFRVDAE (SEQID NO:125), VFRVDAET (SEQ ID NO:126) and VFRVDAETG (SEQ ID NO:127). 22.A modulating agent according to claim 21, wherein the agent comprises alinear peptide having the sequence N-Ac-VFRVDAETG-NH₂ (SEQ ID NO: 127).23. A modulating agent according to claim 21, wherein a cadherin-5 CARsequence is present within a cyclic peptide.
 24. A modulating agentaccording to claim 23, wherein the cyclic peptide comprises a sequenceselected from the group consisting of CDAEC (SEQ ID NO:910), CVDAEC (SEQID NO:911), CDAETC (SEQ ID NO:912), CRVDAEC (SEQ ID NO:913), CVDAETC(SEQ ID NO:914), CRVDAETC (SEQ ID NO:915), CDAETGC (SEQ ID NO:916),CCDAETGC (SEQ ID NO:917), CRVDAETGC (SEQ ID NO:918), CFRVDAEC (SEQ IDNO:919), CFRVDAETC (SEQ ID NO:920), CFRVDAETGC (SEQ ID NO:921),CVFRVDAEC (SEQ ID NO:922), CVFRVDAETC (SEQ ID NO:923), CVFRVDAETGC (SEQID NO:924), DDAEK (SEQ ID NO:925), DVDAEK (SEQ ID NO:926), DRVDAEK (SEQID NO:927), DFRVDAEK (SEQ ID NO:928), DVFRVDAEK (SEQ ID NO:929), EDAEK(SEQ ID NO:930), EVDAEK (SEQ ID NO:931), ERVDAEK (SEQ ID NO:932),EFRVDAEK (SEQ ID NO:933), EVFRVDAEK (SEQ ID NO:934), KDAED (SEQ IDNO:935), KVDAED (SEQ ID NO:936), KDAETD (SEQ ID NO:937), KRVDAED (SEQ IDNO:938), KVDAETD (SEQ ID NO:939), KRVDAETD (SEQ ID NO:940), KDAETGD (SEQID NO:941), KVDAETGD (SEQ ID NO:942), KRVDAETGD (SEQ ID NO:943),KFRVDAED (SEQ ID NO:944), KFRVDAETD (SEQ ID NO:945), KFRVDAETGD (SEQ IDNO:946), KVFRVDAED (SEQ ID NO:947), KVFRVDAETD (SEQ ID NO:948),KVFRVDAETGD (SEQ ID NO:949), VDAEK (SEQ ID NO:950), IDAES (SEQ IDNO:951), VDAES (SEQ ID NO:952), DAETG (SEQ ID NO:953), VDAETG (SEQ IDNO:954), KDAEE (SEQ ID NO:955), KVDAE (SEQ ID NO:956), KDAETE (SEQ IDNO:957), KRVDAE (SEQ ID NO:958), KVDAETE (SEQ ID NO:959), KRVDAETE (SEQID NO:960), KDAETGE (SEQ ID NO:961), KVDAETGE (SEQ ID NO:962), KRVDAETGE(SEQ ID NO:962), KFRVDAE (SEQ ID NO:964), KFRVDAETE (SEQ ID NO:965),KFRVDAETGE (SEQ ID NO:966), KVFRVDAE (SEQ ID NO:967), KVFRVDAETE (SEQ IDNO:968), KVFRVDAETGE (SEQ ID NO:969), VDAET (SEQ ID NO:970), VDAETG (SEQID NO:971), DAETG (SEQ ID NO:972), RVDAE (SEQ ID NO:973), RVDAET (SEQ IDNO:974), RVDAETG (SEQ ID NO:975), FRVDAE (SEQ ID NO:976), FRVDAET (SEQID NO:977), FRVDAETG (SEQ ID NO:978), VFRVDAE (SEQ ID NO:979), VFRVDAET(SEQ ID NO:980) and VFRVDAETG (SEQ ID NO:981).
 25. A polynucleotideencoding a modulating agent according to claim
 21. 26. A modulatingagent comprising an antibody or antigen-binding fragment thereof that:(a) specifically binds to the cadherin-5 CAR sequence VFRVDAETG (SEQ IDNO:127); and (b) modulates a cadherin-5-mediated function.
 27. Amodulating agent according to any one of claims 1-4, wherein the agentcomprises one or more cadherin-6 CAR sequences selected from the groupconsisting NEN, INEN (SEQ ID N0128), NENT (SEQ ID NO:129), IINEN (SEQ IDNO:130), INENT (SEQ ID NO:131), IINENT (SEQ ID NO:132), NENTG (SEQ IDNO:133), INENTG (SEQ ID NO:134), IINENTG (SEQ ID NO:135), FIINEN (SEQ IDNO:136), FIINENT (SEQ ID NO:137), FIINENTG (SEQ ID NO:138), LFIINEN (SEQID NO:139), LFIINENT (SEQ ID NO:140), LFIINENTG (SEQ ID NO:141), EEY,EEYT (SEQ ID NO:142), EEYTG (SEQ ID NO:143), LEEY (SEQ ID NO:144), LEEYT(SEQ ID NO:145), LEEYTG (SEQ ID NO:146), LLEEY (SEQ ID NO:147), LLEEYTG(SEQ ID NO:148), FLLEEY (SEQ ID NO:149), FLLEEYT (SEQ ID NO:150),FLLEEYTG (SEQ ID NO:151), FFLLEEY (SEQ ID NO:152), FFLLEEYT (SEQ IDNO:153), FFLLEEYTG (SEQ ID NO:154), ESE, ESET (SEQ ID NO:155), ESETG(SEQ ID NO:156), VESE (SEQ ID NO:157), VSEST (SEQ ID NO:158), VESETG(SEQ ID NO:159), SVESE (SEQ ID NO:160), SVESET (SEQ ID NO:161), SVESETG(SEQ ID NO:162), FSVESE (SEQ ID NO:163), FSVESET (SEQ ID NO:164),FSVESETG (SEQ ID NO:165), YFSVESE (SEQ ID NO:166), YFSVESET (SEQ IDNO:167), YFSVESETG (SEQ ID NO:168), DSG, DSGN (SEQ ID NO:169), DSGNG(SEQ ID NO:170), IDSG (SEQ ID NO:171), IDSGN (SEQ ID NO:172), IDSGNG(SEQ ID NO:173), NIDSG (SEQ ID NO:174), NIDSGN (SEQ ID NO:175), NIDSGNG(SEQ ID NO:176), FNIDSG (SEQ ID NO:177), FNIDSGN (SEQ ID NO:178),FNIDSGNG (SEQ ID NO:179), IFNIDSG (SEQ ID NO:180), IFNIDSGN (SEQ IDNO:181) and IFNIDSGNG (SEQ ID NO:182).
 28. A modulating agent accordingto claim 27, wherein the agent comprises a linear peptide having thesequence N-Ac-FFLLEEYTG-NH₂ (SEQ ID NO:154), N-Ac-LFIINENTG-NH₂ (SEQ IDNO:141), N-Ac-YFSVESETG-NH₂ (SEQ ID NO:168) or N-Ac-IFNIDSGNG-NH₂ (SEQID NO:182).
 29. A modulating agent according to claim 27, wherein acadherin-6 CAR sequence is present within a cyclic peptide.
 30. Amodulating agent according to claim 29, wherein the cyclic peptidecomprises a sequence selected from the group consisting of: CNENC (SEQID NO:983), CINENC (SEQ ID NO:984), CNENTC (SEQ ID NO:985), CIINENC (SEQID NO:986), CINENTC (SEQ ID NO:987), CIINENTC (SEQ ID NO:988), CNENTGC(SEQ ID NO:989), CINENTGC (SEQ ID NO:990), CIINENTGC (SEQ ID NO:991),CFIINENC (SEQ ID NO:992), CFIINENTC (SEQ ID NO:993), CFIINENTGC (SEQ IDNO:994), CLFIINENC (SEQ ID NO:995), CLFIINENTC (SEQ ID NO:996),CLFIINENTGC (SEQ ID NO:997), DNENK (SEQ ID NO:998), DINENK (SEQ IDNO:999), DIINENK (SEQ ID NO:1000), DFIINENK (SEQ ID NO:1001), DLFIINENK(SEQ ID NO:1002), DNENTK (SEQ ID NO:982), DINENTK (SEQ ID NO:2883),DIINENTK (SEQ ID NO:2884), DFIINENTK (SEQ ID NO:2885), DLFIINENTK (SEQID NO:2946), DNENTGK (SEQ ID NO:2947), DINENTGK (SEQ ID NO:2948),DIINENTGK (SEQ ID NO:3009), DFIINENTGK (SEQ ID NO:3010), DLFIINENTGK(SEQ ID NO:3011), ENENTK (SEQ ID NO:3055), EINENTK (SEQ ID NO:3630),EIINENTK (SEQ ID NO:3736), EFIINENTK (SEQ ID NO:3842), ELFIINENTK (SEQID NO:3890), ENENTGK (SEQ ID NO:3891), EINENTGK (SEQ ID NO:3892),EIINENTGK (SEQ ID NO:3893), EFIINENTGK (SEQ ID NO:3894), ELFIINENTGK(SEQ ID NO:3895), ENENK (SEQ ID NO:1003), EINENK (SEQ ID NO:1004),EIINENK (SEQ ID NO:1005), EFIINENK (SEQ ID NO:1006), ELFIINENK (SEQ IDNO:1007), KNEND (SEQ ID NO:1008), KINEND (SEQ ID NO:1009), KNENTD (SEQID NO:1010), KIINEND (SEQ ID NO:1011), KINENTD (SEQ ID NO:1012),KIINENTD (SEQ ID NO:1013), KNENTGD (SEQ ID NO:1014), KINENTGD (SEQ IDNO:1015), KIINENTGD (SEQ ID NO:1016), KFIINEND (SEQ ID NO:1017),KFIINENTD (SEQ ID NO:1018), KFIINENTGD (SEQ ID NO:1019), KLFIINEND (SEQID NO:1020), KLFIINENTD (SEQ ID NO:1021), KLFIINENTGD (SEQ ID NO:1022),VNENT (SEQ ID NO:1023), INENT (SEQ ID NO:1024), IINENT (SEQ ID NO:1025),NENTG (SEQ ID NO:1026), INENTG (SEQ ID NO:1027) KNENE (SEQ ID NO:1028),KINENE (SEQ ID NO:1029), KNENTE (SEQ ID NO:1030), KIINENE (SEQ IDNO:1031), KINENTE (SEQ ID NO:1032), KIINENTE (SEQ ID NO:1033), KNENTGE(SEQ ID NO:1034), KINENTGE (SEQ ID NO:1035), KIINENTGE (SEQ ID NO:1036),KFIINENE (SEQ ID NO:1037), KFIINENTE (SEQ ID NO:1038), KFIINENTGE (SEQID NO:1039), KLFIINENE (SEQ ID NO:1040), KLFIINENTE (SEQ ID NO:1041),KLFIINENTGE (SEQ ID NO:1042), IINEN (SEQ ID NO:1043), FIINEN (SEQ IDNO:1044), FIINENT (SEQ ID NO:1045), FIINENTG (SEQ ID NO:1046), LFIINEN(SEQ ID NO:1047), LFIINENT (SEQ ID NO:1048), LFIINENTG (SEQ ID NO:1049),CEEYC (SEQ ID NO:1050), CEEYTC (SEQ ID NO:1051), CEEYTGC (SEQ IDNO:1052), CLEEYC (SEQ ID NO:1053), CLEEYTC (SEQ ID NO:1054), CLEEYTGC(SEQ ID NO:1055), CLLEEYC (SEQ ID NO:1056), CLLEEYTGC (SEQ ID NO:1057),CFLLEEYC (SEQ ID NO:1058), CLLEEYTC (SEQ ID NO:1059), CFLLEEYTGC (SEQ IDNO:1060), CFFLLEEYC (SEQ ID NO:1061), CFFLLEEYTC (SEQ ID NO:1062),CFFLLEEYTGC (SEQ ID NO:1063), CESEC (SEQ ID NO:1064), CESETC (SEQ IDNO:1065), CESETGC (SEQ ID NO:1066), CVESEC (SEQ ID NO:1067), CVSESTC(SEQ ID NO:1068), CVESETGC (SEQ ID NO:1069), CSVESEC (SEQ ID NO:1070),CSVESETC (SEQ ID NO:1071), CSVESETGC (SEQ ID NO:1072), CFSVESEC (SEQ IDNO:1073), CFSVESETC (SEQ ID NO:1074), CFSVESETGC (SEQ ID NO:1075),CYFSVESEC (SEQ ID NO:1076), CYFSVESETC (SEQ ID NO:1077), CYFSVESETGC(SEQ ID NO:1078), CDSGC (SEQ ID NO:1079), CDSGNC (SEQ ID NO:1080),CDSGNGC (SEQ ID NO:1081), CIDSGC (SEQ ID NO:1082), CIDSGNC (SEQ IDNO:1083), CIDSGNGC (SEQ ID NO:1084), CNIDSGC (SEQ ID NO:1085), CNIDSGNC(SEQ ID NO:1086), CNIDSGNGC (SEQ ID NO:1087), CFNIDSGC (SEQ ID NO:1088),CFNIDSGNC (SEQ ID NO:1089), CFNIDSGNGC (SEQ ID NO:1090), CIFNIDSGC (SEQID NO:1091), CIFNIDSGNC (SEQ ID NO:1092), CIFNIDSGNGC (SEQ ID NO:1093),KEEYD (SEQ ID NO:1094), KLEEYD (SEQ ID NO:1095), KEEYTD (SEQ IDNO:1096), KEEYTGD (SEQ ID NO:1097), KLEEYTD (SEQ ID NO:1098), KLEEYTGD(SEQ ID NO:1099), KLLEEYD (SEQ ID NO:1100), KLLEEYTGD (SEQ ID NO:1101),KFLLEEYD (SEQ ID NO:1102), KLLEEYTD (SEQ ID NO:1103), KFLLEEYTGD (SEQ IDNO:1104), KFFLLEEYD (SEQ ID NO:1105), KFFLLEEYTD (SEQ ID NO:1106),KFFLLEEYTGD (SEQ ID NO:1107), KESED (SEQ ID NO:1108), KESETD (SEQ IDNO:1109), KESETGD (SEQ ID NO:1110), KVESED (SEQ ID NO:1111), KVSESTD(SEQ ID NO:1112), KVESETGD (SEQ ID NO:1113), KSVESED (SEQ ID NO:1114),KSVESETD (SEQ ID NO:1115), KSVESETGD (SEQ ID NO:1116), KFSVESED (SEQ IDNO:1117), KFSVESETD (SEQ ID NO:1118), KFSVESETGD (SEQ ID NO:1119),KYFSVESED (SEQ ID NO:1120), KYFSVESETD (SEQ ID NO: 1121), KYFSVESETGD(SEQ ID NO:1122), KDSGD (SEQ ID NO:1123), KDSGND (SEQ ID NO:1124),KDSGNGD (SEQ ID NO:1125), KIDSGD (SEQ ID NO:1126), KIDSGND (SEQ IDNO:1127), KIDSGNGD (SEQ ID NO:1128), KNIDSGD (SEQ ID NO:1129), KNIDSGND(SEQ ID NO:1130), KNIDSGNGD (SEQ ID NO:1131), KFNIDSGD (SEQ ID NO:1132),KFNIDSGND (SEQ ID NO:1133), KFNIDSGNGD (SEQ ID NO:1134), KIFNIDSGD (SEQID NO:1135), KIFNIDSGND (SEQ ID NO:1136), KIFNIDSGNGD (SEQ ID NO:1137),EEEYK (SEQ ID NO:1138), EEEYTK (SEQ ID NO:1139), EEEYTGK (SEQ IDNO:1140), ELEEYK (SEQ ID NO:1141), EEEYTK (SEQ ID NO: 1142), ELEEYTGK(SEQ ID NO: 1143), ELLEEYK (SEQ ID NO:1144), ELLEEYTGK (SEQ ID NO:1145),EFLLEEYK (SEQ ID NO:1146), ELLEEYTK (SEQ ID NO:1147), EFLLEEYTGK (SEQ IDNO:1148), EFFLLEEYK (SEQ ID NO:1149), EFFLLEEYTK (SEQ ID NO:1150),EFFLLEEYTGK (SEQ ID NO:1151), EESEK (SEQ ID NO:1152), EESETK (SEQ ID NO:1153), EESETGK (SEQ ID NO:1154), EVESEK (SEQ ID NO:1155), EVSESTK (SEQID NO:1156), EVESETGK (SEQ ID NO:1157), ESVESEK (SEQ ID NO:1158),ESVESETK (SEQ ID NO:1159), ESVESETGK (SEQ ID NO:1160), EFSVESEK (SEQ IDNO:1161), EFSVESETK (SEQ ID NO:1162), EFSVESETGK (SEQ ID NO:1163),EYFSVESEK (SEQ ID NO: 1164), EYFSVESETK (SEQ ID NO: 1165), EYFSVESETGK(SEQ ID NO:1166), EDSGK (SEQ ID NO:1167), EDSGNK (SEQ ID NO:1168),EDSGNGK (SEQ ID NO:1169), EIDSGK (SEQ ID NO:1170), EIDSGNK (SEQ IDNO:1171), EIDSGNGK (SEQ ID NO:1172), ENIDSGK (SEQ ID NO:1173), ENIDSGNK(SEQ ID NO:1174), ENIDSGNGK (SEQ ID NO: 1175), EFNIDSGK (SEQ IDNO:1176), EFNIDSGNK (SEQ ID NO:1177), EFNIDSGNGK (SEQ ID NO:1178),EIFNIDSGK (SEQ ID NO:1179), EIFNIDSGNK (SEQ ID NO:1180), EIFNIDSGNGK(SEQ ID NO:1181), DEEYK (SEQ ID NO: 1182), DLEEYK (SEQ ID NO: 1183),DLEEYTK (SEQ ID NO:1184), DLEEYTGK (SEQ ID NO:1185), DLLEEYK (SEQ IDNO:1186), DLLEEYTGK (SEQ ID NO:1187), DFLLEEYK (SEQ ID NO: 1188),DLLEEYTK (SEQ ID NO:1189), DFLLEEYTGK (SEQ ID NO:1190), DFFLLEEYK (SEQID NO:1191), DFFLLEEYTK (SEQ ID NO:1192), DFFLLEEYTGK (SEQ ID NO:1193),DESEK (SEQ ID NO:1194), DESETK (SEQ ID NO:1195), DESETGK (SEQ IDNO:1196), DVESEK (SEQ ID NO: 1197), DVSESTK (SEQ ID NO: 1198), DVESETGK(SEQ ID NO: 1199), DSVESEK (SEQ ID NO:1200), DSVESETK (SEQ ID NO:1201),DSVESETGK (SEQ ID NO:1202), DFSVESEK (SEQ ID NO:1203), DFSVESETK (SEQ IDNO:1204), DFSVESETGK (SEQ ID NO:1205), DYFSVESEK (SEQ ID NO:1206),DYFSVESETK (SEQ ID NO:1207), DYFSVESETGK (SEQ ID NO:1208), DDSGK (SEQ IDNO:1209), DDSGNK (SEQ ID NO:1210), DDSGNGK (SEQ ID NO:1211), DIDSGK (SEQID NO:1212), DIDSGNK (SEQ ID NO:1213), DIDSGNGK (SEQ ID NO:1214),DNIDSGK (SEQ ID NO:1215), DNIDSGNK (SEQ ID NO:1216), DNIDSGNGK (SEQ IDNO:1217), DFNIDSGK (SEQ ID NO:1218), DFNIDSGNK (SEQ ID NO:1219),DFNIDSGNGK (SEQ ID NO:1220), DIFNIDSGK (SEQ ID NO:1221), DIFNIDSGNK (SEQID NO:1222), DIFNIDSGNGK (SEQ ID NO:1223), KEEYE (SEQ ID NO:1224),KLEEYE (SEQ ID NO:1225), KLEEYTE (SEQ ID NO:1226), KLEEYTGE (SEQ IDNO:1227), KLLEEYE (SEQ ID NO:1228), KLLEEYTGE (SEQ ID NO:1229), KFLLEEYE(SEQ ID NO:1230), KLLEEYTE (SEQ ID NO:1231), KFLLEEYTGE (SEQ IDNO:1232), KFFLLEEYE (SEQ ID NO:1233), KFFLLEEYTE (SEQ ID NO:1234),KFFLLEEYTGE (SEQ ID NO: 1235), KNENE (SEQ ID NO:1236), KNENTE (SEQ IDNO:1237), KINENTGE (SEQ ID NO:1238), KESEE (SEQ ID NO:1239), KESETE (SEQID NO:1240), KESETGE (SEQ ID NO:1241), KVESEE (SEQ ID NO:1242) KVSESTE(SEQ ID NO:1243), KVESETGE (SEQ ID NO:1244), KSVESEE (SEQ ID NO:1245),KSVESETE (SEQ ID NO:1246), KSVESETGE (SEQ ID NO:1247), KFSVESEE (SEQ IDNO:1248), KFSVESETE (SEQ ID NO:1249), KFSVESETGE (SEQ ID NO:1250),KYFSVESEE (SEQ ID NO:1251), KYFSVESETE (SEQ ID NO:1252), KYFSVESETGE(SEQ ID NO:1253), KDSGE (SEQ ID NO:1254), KDSGNE (SEQ ID NO:1255),KDSGNGE (SEQ ID NO:1256), KIDSGE (SEQ ID NO:1257), KIDSGNE (SEQ IDNO:1258), KIDSGNGE (SEQ ID NO:1259), KNIDSGE (SEQ ID NO:1260), KNIDSGNE(SEQ ID NO:1261), KNIDSGNGE (SEQ ID NO:1262), KFNIDSGE (SEQ ID NO:1263),KFNIDSGNE (SEQ ID NO:1264), KFNIDSGNGE (SEQ ID NO:1265), KIFNIDSGE (SEQID NO:1266), KIFNIDSGNE (SEQ ID NO:1267), KIFNIDSGNGE (SEQ ID NO:1268),LEEYT (SEQ ID NO:1269), LEEYTG (SEQ ID NO:1270), LLEEY (SEQ ID NO:1271),LLEEYTG (SEQ ID NO:1272), FLLEEY (SEQ ID NO:1273), LLEEYT (SEQ IDNO:1274), FLLEEYTG (SEQ ID NO:1275), FFLLEEY (SEQ ID NO:1276), FFLLEEYT(SEQ ID NO:1277), FFLLEEYTG (SEQ ID NO:1278), ESETG (SEQ ID NO:1279),VSEST (SEQ ID NO:1280), VESETG (SEQ ID NO:1281), SVESE (SEQ ID NO:1282),SVESET (SEQ ID NO:1283), SVESETG (SEQ ID NO:1284), FSVESE (SEQ IDNO:1285), FSVESET (SEQ ID NO:1286), FSVESETG (SEQ ID NO:1287), YFSVESE(SEQ ID NO:1288), YFSVESET (SEQ ID NO:1289), YFSVESETG (SEQ ID NO:1290),DSGNG (SEQ ID NO:1291), IDSGN (SEQ ID NO:1292), IDSGNG (SEQ ID NO:1293),NIDSG (SEQ ID NO:1294), NIDSGN (SEQ ID NO:1295), NIDSGNG (SEQ IDNO:1296), FNIDSG (SEQ ID NO:1297), FNIDSGN (SEQ ID NO:1298), FNIDSGNG(SEQ ID NO:1299), IFNIDSG (SEQ ID NO:1300), IFNIDSGN (SEQ ID NO:1301)and IFNIDSGNG (SEQ ID NO:1302).
 31. A polynucleotide encoding amodulating agent according to claim
 27. 32. A modulating agentcomprising an antibody or antigen-binding fragment thereof that: (a)specifically binds to a cadherin-6 CAR sequence selected from the groupconsisting of FFLLEEYTG (SEQ ID NO:154), LFIINENTG (SEQ ID NO:141),YFSVESETG (SEQ ID NO:168) and IFNIDSGNG (SEQ ID NO:182); and (b)modulates a cadherin-6-mediated function.
 33. A modulating agentaccording to any one of claims 1-4, wherein the agent comprises one ormore cadherin-7 CAR sequences selected from the group consisting of DEN,IDEN (SEQ ID NO:183), DENT (SEQ ID NO:184), IIDEN (SEQ ID NO:185), IDENT(SEQ ID NO:186), IIDENT (SEQ ID NO:187), DENTG (SEQ ID NO:188), IDENTG(SEQ ID NO:189), IIDENTG (SEQ ID NO:190), FIIDEN (SEQ ID NO:191),FIIDENT (SEQ ID NO:192), FIIDENTG (SEQ ID NO:193), IFIIDEN (SEQ IDNO:194), IFIIDENT (SEQ ID NO:195), IFIIDENTG (SEQ ID NO:196), EPK, EPKT(SEQ ID NO:197), EPKTG (SEQ ID NO:198), VEPK (SEQ ID NO:199), VEPKT (SEQID NO:200), VEPKTG (SEQ ID NO:201), SVEPK (SEQ ID NO:202), SVEPKT (SEQID NO:203), SVEPKTG (SEQ ID NO:204), FSVEPK (SEQ ID NO:205), FSVEPKT(SEQ ID NO:206), FSVEPKTG (SEQ ID NO:207), YFSVEPK (SEQ ID NO:208),YFSVEPKT (SEQ ID NO:209), YFSVEPKTG (SEQ ID NO:210), DAN, DANS (SEQ IDNO:211), DANSG (SEQ ID NO:212), IDAN (SEQ ID NO:213), IDANS (SEQ IDNO:214), IDANSG (SEQ ID NO:215), NIDAN (SEQ ID NO:216), NIDANS (SEQ IDNO:217), NIDANSG (SEQ ID NO:218), FNIDAN (SEQ ID NO:219), FNIDANS (SEQID NO:220), FNIDANSG (SEQ ID NO:221), YFNIDAN (SEQ ID NO:222), YFNIDANS(SEQ ID NO:223) and YFNIDANSG (SEQ ID NO:224).
 34. A modulating agentaccording to claim 33, wherein the agent comprises a linear peptidehaving the sequence N-Ac-IFIIDENTG-NH₂ (SEQ ID NO:196),N-Ac-YFSVEPKTG-NH₂ (SEQ ID NO:210) or N-Ac-YFNIDANSG-NH₂ (SEQ IDNO:224).
 35. A modulating agent according to claim 33, wherein acadherin-7 CAR sequence is present within a cyclic peptide.
 36. Amodulating agent according to claim 35, wherein the cyclic peptidecomprises a sequence selected from the group consisting of CDENC (SEQ IDNO:1303), CIDENC (SEQ ID NO:1304), CDENTC (SEQ ID NO:1305), CIIDENC (SEQID NO:1306), CIDENTC (SEQ ID NO:1307), CIIDENTC (SEQ ID NO:1308),CDENTGC (SEQ ID NO:1309), CIDENTGC (SEQ ID NO:1310), CIIDENTGC (SEQ IDNO:1311), CFIIDENC (SEQ ID NO:1312), CFIIDENTC (SEQ ID NO:1313),CFIIDENTGC (SEQ ID NO:1314), CIFIIDENC (SEQ ID NO:1315), CIFIIDENTC (SEQID NO:1316), CIFIIDENTGC (SEQ ID NO:1317), DDENK (SEQ ID NO:1319),DIDENK (SEQ ID NO:1320), DIIDENK (SEQ ID NO:1321), DFIIDENK (SEQ IDNO:1322), DIFIIDENK (SEQ ID NO: 1323), DDENTK (SEQ ID NO: 1318), DIDENTK(SEQ ID NO: 1344), DIIDENTK (SEQ ID NO:3896), DFIIDENTK (SEQ IDNO:3897), DIFIIDENTK (SEQ ID NO:3898), DDENTGK (SEQ ID NO:3899),DIDENTGK (SEQ ID NO:3900), DIIDENTGK (SEQ ID NO:3901), DFIIDENTGK (SEQID NO:3902), DIFIIDENTGK (SEQ ID NO:3903), EDENTK (SEQ ID NO:3904),EIDENTK (SEQ ID NO:3905), EIIDENTK (SEQ ID NO:3906), EFIIDENTK (SEQ IDNO:3907), EIFIIDENTK (SEQ ID NO:3908), EDENTGK (SEQ ID NO:3909),EIDENTGK (SEQ ID NO:3910), EIIDENTGK (SEQ ID NO:3911), EFIIDENTGK (SEQID NO:3912), EIFIIDENTGK (SEQ ID NO:3913), EDENK (SEQ ID NO:1324),EIDENK (SEQ ID NO:1325), EIIDENK (SEQ ID NO:1326), EFIIDENK (SEQ IDNO:1327), EIFIIDENK (SEQ ID NO:1328), KDEND (SEQ ID NO:1329), KIDEND(SEQ ID NO:1330), KDENTD (SEQ ID NO:1331), KIIDEND (SEQ ID NO:1332),KIDENTD (SEQ ID NO:1333), KIIDENTD (SEQ ID NO:1334), KDENTGD (SEQ IDNO:1335), KIDENTGD (SEQ ID NO:1336), KIIDENTGD (SEQ ID NO:1337),KFIIDEND (SEQ ID NO:1338), KFIIDENTD (SEQ ID NO:1339), KFIIDENTGD (SEQID NO:1340), KIFIIDEND (SEQ ID NO:1341), KIFIIDENTD (SEQ ID NO:1342),KIFIIDENTGD (SEQ ID NO:1343), IDENT (SEQ ID NO:1345), IIDENT (SEQ IDNO:1346), DENTG (SEQ ID NO:1347), IDENTG (SEQ ID NO:1348) KDENE (SEQ IDNO:1349), KIDENE (SEQ ID NO:1350), KDENTE (SEQ ID NO:1351), KIIDENE (SEQID NO:1352), KIDENTE (SEQ ID NO:1353), KIIDENTE (SEQ ID NO:1354),KDENTGE (SEQ ID NO:1355), KIDENTGE (SEQ ID NO:1356), KIIDENTGE (SEQ IDNO:1357), KFIIDENE (SEQ ID NO:1358), KFIIDENTE (SEQ ID NO:1359),KFIIDENTGE (SEQ ID NO:1360), KIFIIDENE (SEQ ID NO:1361), KIFIIDENTE (SEQID NO:1362), KIFIIDENTGE (SEQ ID NO:1363), DDENTK (SEQ ID NO:1364),IIDEN (SEQ ID NO:1365), IIDENTG (SEQ ID NO:1366), FIIDEN (SEQ IDNO:1367), FIIDENT (SEQ ID NO:1368), FIIDENTG (SEQ ID NO:1369), IFIIDEN(SEQ ID NO:1370), IFIIDENT (SEQ ID NO:1371), IFIIDENTG (SEQ ID NO:1372),CEPKC (SEQ ID NO:1373), CEPKTC (SEQ ID NO:1374), CEPKTGC (SEQ IDNO:1375), CVEPKC (SEQ ID NO:1376), CVEPKTC (SEQ ID NO:1377), CVEPKTGC(SEQ ID NO:1378), CSVEPKC (SEQ ID NO:1379), CSVEPKTC (SEQ ID NO:1380),CSVEPKTGC (SEQ ID NO:1381), CFSVEPKC (SEQ ID NO:1382), CFSVEPKTC (SEQ IDNO:1383), CFSVEPKTGC (SEQ ID NO:1384), CYFSVEPKC (SEQ ID NO:1385),CYFSVEPKTC (SEQ ID NO:1386), CYFSVEPKTGC (SEQ ID NO:1387), CDANC (SEQ IDNO:1388), CDANSC (SEQ ID NO:1389), CDANSGC (SEQ ID NO:1390), CIDANC (SEQID NO:1391), CIDANSC (SEQ ID NO:1392), CIDANSGC (SEQ ID NO:1393),CNIDANC (SEQ ID NO:1394), CNIDANSC (SEQ ID NO:1395), CNIDANSGC (SEQ IDNO:1396), CFNIDANC (SEQ ID NO:1397), CFNIDANSC (SEQ ID NO:1398),CFNIDANSGC (SEQ ID NO:1399), CYFNIDANC (SEQ ID NO:1400), CYFNIDANSC (SEQID NO:1401), CYFNIDANSGC (SEQ ID NO: 1402), EEPKK (SEQ ID NO: 1403),EEPKTK (SEQ ID NO:1404), EEPKTGK (SEQ ID NO:1405), EVEPKK (SEQ IDNO:1406), EVEPKTK (SEQ ID NO:1407), EVEPKTGK (SEQ ID NO:1408), ESVEPKK(SEQ ID NO:1409), ESVEPKTK (SEQ ID NO:1410), ESVEPKTGK (SEQ ID NO:1411),EFSVEPKK (SEQ ID NO:1412), EFSVEPKTK (SEQ ID NO:1413), EFSVEPKTGK (SEQID NO:1414), EYFSVEPKK (SEQ ID NO:1415), EYFSVEPKTK (SEQ ID NO:1416),EYFSVEPKTGK (SEQ ID NO:1417), EDANK (SEQ ID NO:1418), EDANSK (SEQ IDNO:1419), EDANSGK (SEQ ID NO:1420), EIDANK (SEQ ID NO:1421), EIDANSK(SEQ ID NO:1422), EIDANSGK (SEQ ID NO:1423), ENIDANK (SEQ ID NO:1424),ENIDANSK (SEQ ID NO:1425), ENIDANSGK (SEQ ID NO:1426), EFNIDANK (SEQ IDNO:1427), EFNIDANSK (SEQ ID NO:1428), EFNIDANSGK (SEQ ID NO:1429),EYFNIDANK (SEQ ID NO:1430), EYFNIDANSK (SEQ ID NO:1431), EYFNIDANSGK(SEQ ID NO:1432), KDAND (SEQ ID NO:1433), KIDAND (SEQ ID NO:1434),KDANSD (SEQ ID NO:1435), KNIDAND (SEQ ID NO:1436), KIDANSD (SEQ IDNO:1437), KNIDANSD (SEQ ID NO:1438), KDANSGD (SEQ ID NO:1439), KIDANSGD(SEQ ID NO:1440), KNIDANSGD (SEQ ID NO:1441), KFNIDAND (SEQ ID NO:1442),KFNIDANSD (SEQ ID NO:1443), KFNIDANSGD (SEQ ID NO:1444), KYFNIDAND (SEQID NO:1445), KYFNIDANSD (SEQ ID NO:1446), KYFNIDANSGD (SEQ ID NO:1447),KEPKD (SEQ ID NO:1448), KEPKTD (SEQ ID NO:1449), KEPKTGD (SEQ IDNO:1450), KVEPKD (SEQ ID NO:1451), KVEPKTD (SEQ ID NO:1452), KVEPKTGD(SEQ ID NO:1453), KSVEPKD (SEQ ID NO:1454), KSVEPKTD (SEQ ID NO:1455),KSVEPKTGD (SEQ ID NO:1456), KFSVEPKD (SEQ ID NO:1457), KFSVEPKTD (SEQ IDNO:1458), KFSVEPKTGD (SEQ ID NO:1459), KYFSVEPKD (SEQ ID NO:1460),KYFSVEPKTD (SEQ ID NO:1461), KYFSVEPKTGD (SEQ ID NO:1462), KDAND (SEQ IDNO: 1463), KDANSD (SEQ ID NO:1464), KDANSGD (SEQ ID NO:1465), KIDAND(SEQ ID NO:1466), KIDANSD (SEQ ID NO:1467), KIDANSGD (SEQ ID NO:1468),KNIDAND (SEQ ID NO:1469), KNIDANSD (SEQ ID NO:1470), KNIDANSGD (SEQ IDNO:1471), KFNIDAND (SEQ ID NO:1472), KFNIDANSD (SEQ ID NO:1473),KFNIDANSGD (SEQ ID NO:1474), KYFNIDAND (SEQ ID NO:1475), KYFNIDANSD (SEQID NO:1476), KYFNIDANSGD (SEQ ID NO: 1477), DEPKK (SEQ ID NO:1478),DEPKTK (SEQ ID NO:1479), DEPKTGK (SEQ ID NO:1480), DVEPKK (SEQ IDNO:1481), DVEPKTK (SEQ ID NO:1482), DVEPKTGK (SEQ ID NO:1483), DSVEPKK(SEQ ID NO:1484), DSVEPKTK (SEQ ID NO:1485), DSVEPKTGK (SEQ ID NO:1486),DFSVEPKK (SEQ ID NO:1487), DFSVEPKTK (SEQ ID NO:1488), DFSVEPKTGK (SEQID NO:1489), DYFSVEPKK (SEQ ID NO:1490), DYFSVEPKTK (SEQ ID NO:1491),DYFSVEPKTGK (SEQ ID NO:1492), DDANK (SEQ ID NO:1493), DDANSK (SEQ IDNO:1494), DDANSGK (SEQ ID NO:1495), DIDANK (SEQ ID NO:1496), DIDANSK(SEQ ID NO:1497), DIDANSGK (SEQ ID NO:1498), DNIDANK (SEQ ID NO:1499),DNIDANSK (SEQ ID NO:1500), DNIDANSGK (SEQ ID NO:1501), DFNIDANK (SEQ IDNO:1502), DFNIDANSK (SEQ ID NO:1503), DFNIDANSGK (SEQ ID NO:1504),DYFNIDANK (SEQ ID NO:1505), DYFNIDANSK (SEQ ID NO:1506), DYFNIDANSGK(SEQ ID NO:1507), KDENE (SEQ ID NO:1508), KDENTE (SEQ ID NO:1509),KDENTGE (SEQ ID NO:1510), KIDENE (SEQ ID NO:1511), KIDENTE (SEQ IDNO:1512), KIDENTGE (SEQ ID NO:1513), KIIDENE (SEQ ID NO:1514), KIIDENTE(SEQ ID NO:1515), KIIDENTGE (SEQ ID NO:1516), KFIIDENE (SEQ ID NO:1517),KFIIDENTE (SEQ ID NO:1518), KFIIDENTGE (SEQ ID NO:1519), KIFIIDENE (SEQID NO:1520), KIFIIDENTE (SEQ ID NO:1521), KIFIIDENTGE (SEQ ID NO:1522),KEPKE (SEQ ID NO:1523), KEPKTE (SEQ ID NO:1524), KEPKTGE (SEQ IDNO:1525), KVEPKE (SEQ ID NO:1526), KVEPKTE (SEQ ID NO:1527), KVEPKTGE(SEQ ID NO:1528), KSVEPKE (SEQ ID NO:1529), KSVEPKTE (SEQ ID NO:1530),KSVEPKTGE (SEQ ID NO: 1531), KFSVEPKE (SEQ ID NO: 1532), KFSVEPKTE (SEQID NO: 1533), KFSVEPKTGE (SEQ ID NO:1534), KYFSVEPKE (SEQ ID NO:1535),KYFSVEPKTE (SEQ ID NO:1536), KYFSVEPKTGE (SEQ ID NO:1537), KDANE (SEQ IDNO:1538), KDANSE (SEQ ID NO:1539), KDANSGE (SEQ ID NO:1540), KIDANE (SEQID NO:1541), KIDANSE (SEQ ID NO:1542), KIDANSGE (SEQ ID NO:1543),KNIDANE (SEQ ID NO:1544), KNIDANSE (SEQ ID NO:1545), KNIDANSGE (SEQ IDNO:1546), KFNIDANE (SEQ ID NO:1547), KFNIDANSE (SEQ ID NO:1548),KFNIDANSGE (SEQ ID NO:1549), KYFNIDANE (SEQ ID NO:1550), KYFNIDANSE (SEQID NO:1551), KYFNIDANSGE (SEQ ID NO:1552), DENTG (SEQ ID NO:1553), IDENT(SEQ ID NO:1554), IDENTG (SEQ ID NO:1555), IIDEN (SEQ ID NO:1556),IIDENT (SEQ ID NO:1557), IDENTG (SEQ ID NO:1558), FIIDEN (SEQ IDNO:1559), FIIDENT (SEQ ID NO:1560), FIIDENTG (SEQ ID NO:1561), IFIIDEN(SEQ ID NO:1562), IFIIDENT (SEQ ID NO:1563), IFIIDENTG (SEQ ID NO:1564),EPKTG (SEQ ID NO:1565), VEPKT (SEQ ID NO:1566), VEPKTG (SEQ ID NO:1567),SVEPK (SEQ ID NO:1568), SVEPKT (SEQ ID NO:1569), SVEPKTG (SEQ IDNO:1570), FSVEPK (SEQ ID NO:1571), FSVEPKT (SEQ ID NO:1572), FSVEPKTG(SEQ ID NO:1573), YFSVEPK (SEQ ID NO:1574), YFSVEPKT (SEQ ID NO:1575),YFSVEPKTG (SEQ ID NO:1576), DANSG (SEQ ID NO:1577), IDANS (SEQ IDNO:1578), IDANSG (SEQ ID NO:1579), NIDAN (SEQ ID NO:1580), NIDANS (SEQID NO:1581), NIDANSG (SEQ ID NO:1582), FNIDAN (SEQ ID NO:1583), FNIDANS(SEQ ID NO:1584), FNIDANSG (SEQ ID NO:1585), YFNIDAN (SEQ ID NO:1586),YFNIDANS (SEQ ID NO:1587) and YFNIDANSG (SEQ ID NO: 1588).
 37. Apolynucleotide encoding a modulating agent according to claim
 33. 38. Amodulating agent comprising an antibody or antigen-binding fragmentthereof that: (a) specifically binds to a cadherin-7 CAR sequenceselected from the group consisting of IFIIDENTG (SEQ ID NO:196),YFSVEPKTG (SEQ ID NO:210) and YFNIDANSG (SEQ ID NO:224); and (b)modulates a cadherin-7-mediated function.
 39. A modulating agentaccording to any one of claims 1-4, wherein the agent comprises one ormore cadherin-8 CAR sequences selected from the group consisting NDV,INDV (SEQ ID NO:225), NDVT (SEQ ID NO:226), QINDV (SEQ ID NO:227), INDVT(SEQ ID NO:228), QINDVT (SEQ ID NO:229), NDVTG (SEQ ID NO:230), INDVTG(SEQ ID NO:231), QINDVTG (SEQ ID NO:232), FQINDV (SEQ ID NO:233),FQINDVT (SEQ ID NO:234), FQINDVTG (SEQ ID NO:235), IFQINDV (SEQ IDNO:236), IFQINDVT (SEQ ID NO:237), IFQINDVTG (SEQ ID NO:238), EEF, EEFS(SEQ ID NO:239), EEFSG (SEQ ID NO:240), LEEF (SEQ ID NO:241), LEEFS (SEQID NO:242), LEEFSG (SEQ ID NO:243), VLEEF (SEQ ID NO:244), VLEEFS (SEQID NO:245), VLEEFSG (SEQ ID NO:247), FVLEEF (SEQ ID NO:247), FVLEEFS(SEQ ID NO:248), FVLEEFSG (SEQ ID NO:249), MFVLEEF (SEQ ID NO:250),MFVLEEFS (SEQ ID NO:251) and MFVLEEFSG (SEQ ID NO:252).
 40. A modulatingagent according to claim 39, wherein the agent comprises a linearpeptide having the sequence N-Ac-MFVLEEFSG-NH₂ (SEQ ID NO:252) orN-Ac-IFQINDVTG-NH₂ (SEQ ID NO:238).
 41. A modulating agent according toclaim 39, wherein a cadherin-8 CAR sequence is present within a cyclicpeptide.
 42. A modulating agent according to claim 41, wherein thecyclic peptide comprises a sequence selected from the group consistingof CNDVC (SEQ ID NO:1589), CINDVC (SEQ ID NO:1590), CNDVTC (SEQ IDNO:1591), CQINDVC (SEQ ID NO: 1592), CINDVTC (SEQ ID NO: 1593), CQINDVTC(SEQ ID NO: 1594), CNDVTGC (SEQ ID NO:1595), CINDVTGC (SEQ ID NO:1596),CQINDVTGC (SEQ ID NO:1597), CFQINDVC (SEQ ID NO:1598), CFQINDVTC (SEQ IDNO:1599), CFQINDVTGC (SEQ ID NO:1600), CIFQINDVC (SEQ ID NO:1601),CIFQINDVTC (SEQ ID NO:1602), CIFQINDVTGC (SEQ ID NO:1603), DNDVK (SEQ IDNO: 1604), DINDVK (SEQ ID NO:1605), DQINDVK (SEQ ID NO:1606), DFQINDVK(SEQ ID NO:1607), DIFQINDVK (SEQ ID NO:1608), DNDVTK (SEQ ID NO:3924),DINDVTK (SEQ ID NO:3925), DQINDVTK (SEQ ID NO:3926), DFQINDVTK (SEQ IDNO:3927), DIFQINDVTK (SEQ ID NO:3928), DNDVTGK (SEQ ID NO:3929),DINDVTGK (SEQ ID NO:3930), DQINDVTGK (SEQ ID NO:3931), DFQINDVTGK (SEQID NO:3932), DIFQINDVTGK (SEQ ID NO:3933), ENDVTK (SEQ ID NO:3914),EINDVTK (SEQ ID NO:3915), EQINDVTK (SEQ ID NO:3916), EFQINDVTK (SEQ IDNO:3917), EIFQINDVTK (SEQ ID NO:3918), ENDVTGK (SEQ ID NO:3919),EINDVTGK (SEQ ID NO:3920), EQINDVTGK (SEQ Ib NO:3921), EFQINDVTGK (SEQID NO:3922), EIFQINDVTGK (SEQ ID NO:3923), ENDVK (SEQ ID NO:1609),EINDVK (SEQ ID NO:1610), EQINDVK (SEQ ID NO:1611), EFQINDVK (SEQ IDNO:1612), EIFQINDVK (SEQ ID NO:1613), KNDVD (SEQ ID NO:1614), KINDVD(SEQ ID NO:1615), KNDVTD (SEQ ID NO:1616), KQINDVD (SEQ ID NO:1617),KINDVTD (SEQ ID NO:1618), KQINDVTD (SEQ ID NO:1619), KNDVTGD (SEQ IDNO:1620), KINDVTGD (SEQ ID NO:1621), KQINDVTGD (SEQ ID NO:1622),KFQINDVD (SEQ ID NO:1623), KFQINDVTD (SEQ ID NO:1624), KFQINDVTGD (SEQID NO:1625), KIFQINDVD (SEQ ID NO: 1626), KIFQINDVTD (SEQ ID NO:1627),KIFQINDVTGD (SEQ ID NO:1628), VNDVT (SEQ ID NO:1629), INDVT (SEQ IDNO:1630), QINDVT (SEQ ID NO:1631), NDVTG (SEQ ID NO:1632), INVTG (SEQ IDNO:1633) KNDVE (SEQ ID NO:1634), KINDVE (SEQ ID NO:1635), KNDVTE (SEQ IDNO:1636), KQINDVE (SEQ ID NO:1637), KINDVTE (SEQ ID NO:1638), KQINDVTE(SEQ ID NO:1639), KNDVTGE (SEQ ID NO:1640), KINDVTGE (SEQ ID NO:1641),KQINDVTGE (SEQ ID NO:1642), KFQINDVE (SEQ ID NO:1643), KFQINDVTE (SEQ IDNO:1644), KFQINDVTGE (SEQ ID NO:1645), KIFQINDVE (SEQ ID NO:1646),KIFQINDVTE (SEQ ID NO:1647), KIFQINDVTGE (SEQ ID NO:1648), CEEFC (SEQ IDNO:1649), CEEFSC (SEQ ID NO:1650), CEEFSGC (SEQ ID NO:1651), CLEEFC (SEQID NO:1652), CLEEFSC (SEQ ID NO:1653), CLEEFSGC (SEQ ID NO:1654),CVLEEFC (SEQ ID NO:1655), CVLEEFSC (SEQ ID NO:1656), CVLEEFSGC (SEQ IDNO:1657), CFVLEEFC (SEQ ID NO:1658), CFVLEEFSC (SEQ ID NO:1659),CFVLEEFSGC (SEQ ID NO:1660), CMFVLEEFC (SEQ ID NO:1661), CMFVLEEFSC (SEQID NO:1662), CMFVLEEFSGC (SEQ ID NO:1663), EEEFK (SEQ ID NO:1664),EEEFSK (SEQ ID NO:1665), EEEFSGK (SEQ ID NO:1666), ELEEFK (SEQ IDNO:1667), ELEEFSK (SEQ ID NO:1668), ELEEFSGK (SEQ ID NO:1669), EVLEEFK(SEQ ID NO:1670), EVLEEFSK (SEQ ID NO:1671), EVLEEFSGK (SEQ ID NO:1672),EFVLEEFK (SEQ ID NO:1673), EFVLEEFSK (SEQ ID NO:1674), EFVLEEFSGK (SEQID NO:1675), EMFVLEEFK (SEQ ID NO:1676) EMFVLEEFSK (SEQ ID NO:1677),EMFVLEEFSGK (SEQ ID NO:1678)₁ KEEFD (SEQ ID NO:1679), KEEFSD (SEQ IDNO:1680), KEEFSGD (SEQ ID NO:1681), KLEEFD (SEQ ID NO:1682), KLEEFSD(SEQ ID NO:1683), KLEEFSGD (SEQ ID NO:1684), KVLEEFD (SEQ ID NO:1685),KVLEEFSD (SEQ ID NO:1686), KVLEEFSGD (SEQ ID NO:1687), KFVLEEFD (SEQ IDNO:1688), KFVLEEFSD (SEQ ID NO:1689), KFVLEEFSGD (SEQ ID NO:1690),KMFVLEEFD (SEQ ID NO:1691), KMFVLEEFSD (SEQ ID NO:1692), KMFVLEEFSGD(SEQ ID NO:1693)₁ DEEFK (SEQ ID NO:1694), DEEFSK (SEQ ID NO:1695),DEEFSGK (SEQ ID NO:1696), DLEEFK (SEQ ID NO:1697), DLEEFSK (SEQ IDNO:1698), DLEEFSGK (SEQ ID NO:1699), DVLEEFK (SEQ ID NO:1700), DVLEEFSK(SEQ ID NO:1701), DVLEEFSGK (SEQ ID NO:1702), DFVLEEFK (SEQ ID NO:1703),DFVLEEFSK (SEQ ID NO:1704), DFVLEEFSGK (SEQ ID NO:1705), DMFVLEEFK (SEQID NO:1706), DMFVLEEFSK (SEQ ID NO:1707), DMFVLEEFSGK (SEQ ID NO:1708),KEEFE (SEQ ID NO:1709), KEEFSE (SEQ ID NO:1710), KEEFSGE (SEQ IDNO:1711), KLEEFE (SEQ ID NO:1712), KLEEFSE (SEQ ID NO:1713), KLEEFSGE(SEQ ID NO:1714), KVLEEFE (SEQ ID NO:1715), KVLEEFSE (SEQ ID NO:1716),KVLEEFSGE (SEQ ID NO:1717), KFVLEEFE (SEQ ID NO:1718), KFVLEEFSE (SEQ IDNO:1719), KFVLEEFSGE (SEQ ID NO:1720), KMFVLEEFE (SEQ ID NO:1721),KMFVLEEFSE (SEQ ID NO:1722), KMFVLEEFSGE (SEQ ID NO:1723), EEFSG (SEQ IDNO:1724), LEEFS (SEQ ID NO:1725), LEEFSG (SEQ ID NO:1726), VLEEF (SEQ IDNO:1727), VLEEFS (SEQ ID NO:1728), VLEEFSG (SEQ ID NO:1729), FVLEEF (SEQID NO:1730), FVLEEFS (SEQ ID NO:1731), FVLEEFSG (SEQ ID NO:1732),MFVLEEF (SEQ ID NO:1733), MFVLEEFS (SEQ ID NO:1734) and MFVLEEFSG (SEQID Nb:1735).
 43. A polynucleotide encoding a modulating agent accordingto claim
 39. 44. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to acadherin-8 CAR sequence selected from the group consisting of MFVLEEFSG(SEQ ID NO:252) and IFQINDVTG (SEQ ID NO:238); and (b) modulates acadherin-8-mediated function.
 45. A modulating agent according to anyone of claims 1-4, wherein the agent comprises one or more cadherin-12CAR sequences selected from the group consisting of DET, IDET (SEQ IDNO:253), DETT (SEQ ID NO:254), TIDET (SEQ ID NO:255), IDETT (SEQ IDNO:256), TIDETT (SEQ ID NO:257), DETTG (SEQ ID NO:258), IDETTG (SEQ IDNO:259), TIDETTG (SEQ ID NO:260), FTIDET (SEQ ID NO:261), FTIDETT (SEQID NO:262), FTIDETTG (SEQ ID NO:263), VFTIDET (SEQ ID NO:264), VFTIDETT(SEQ ID NO:265), VFTIDETTG (SEQ ID NO:266), DPK, DPKT (SEQ ID NO:267),DPKTG (SEQ ID NO:268), IDPK (SEQ ID NO:269), IDPKT (SEQ ID NO:270),IDPKTG (SEQ ID NO:271), SIDPK (SEQ ID NO:272), SIDPKT (SEQ ID NO:273),SIDPKTG (SEQ ID NO:274), FSIDPK (SEQ ID NO:275), FSIDPKT (SEQ IDNO:276), FSIDPKTG (SEQ ID NO:277), YFSIDPK (SEQ ID NO:278), YFSIDPKT(SEQ ID NO:279) and YFSIDPKTG (SEQ ID NO:280).
 46. A modulating agentaccording to claim 45, wherein the agent comprises a linear peptidehaving the sequence N-Ac-VFTIDETTG-NH₂ (SEQ ID NO:266) orN-Ac-YFSIDPKTG-NH₂ (SEQ ID NO:280).
 47. A modulating agent according toclaim 45, wherein a cadherin-12 CAR sequence is present within a cyclicpeptide.
 48. A modulating agent according to claim 47, wherein thecyclic peptide comprises a sequence selected from the group consistingof CDETC (SEQ ID NO:1736), CIDETC (SEQ ID NO:1737), CDETTC (SEQ IDNO:1738), CTIDETC (SEQ ID NO:1739), CIDETTC (SEQ ID NO:1740), CTIDETTC(SEQ ID NO:1741), CDETTGC (SEQ ID NO:1742), CIDETTGC (SEQ ID NO:1743),CTIDETTGC (SEQ ID NO:1744), CFTIDETC (SEQ ID NO:1745), CFTIDETTC (SEQ IDNO:1746), CFTIDETTGC (SEQ ID NO:1747), CVFTIDETC (SEQ ID NO:1748),CVFTIDETTC (SEQ ID NO:1749), CVFTIDETTGC (SEQ ID NO:1750), DDETK (SEQ IDNO:1752), DIDETK (SEQ ID NO:1753), DTIDETK (SEQ ID NO:1754), DFTIDETK(SEQ ID NO:1755), DVFTIDETK (SEQ ID NO:1756), EDETK (SEQ ID NO:1757),EIDETK (SEQ ID NO:1758), ETIDETK (SEQ ID NO:1759), EFTIDETK (SEQ IDNO:1760), EVFTIDETK (SEQ ID NO:1761), KDETD (SEQ ID NO:1762), KIDETD(SEQ ID NO:1763), KDETTD (SEQ ID NO:1764), KTIDETD (SEQ ID NO:1765),KIDETTD (SEQ ID NO:1766), KTIDETTD (SEQ ID NO:1767), KDETTGD (SEQ IDNO:1768), KIDETTGD (SEQ ID NO:1769), KTIDETTGD (SEQ ID NO:1770),KFTIDETD (SEQ ID NO:1771), KFTIDETTD (SEQ ID NO:1772), KFTIDETTGD (SEQID NO:1773), KVFTIDETD (SEQ ID NO:1774), KVFTIDETTD (SEQ ID NO: 1775),KVFTIDETTGD (SEQ ID NO:1776), DDETTK (SEQ ID NO: 1751), DIDETTK (SEQ IDNO:1777), DTIDETTK (SEQ ID NO:3934), DFTIDETTK (SEQ ID NO:3935),DVFTIDETTK (SEQ ID NO:3936), DDETTGK (SEQ ID NO:3937), DIDETTGK (SEQ IDNO:3938), DTIDETTGK (SEQ ID NO:3939), DFTIDETTGK (SEQ ID NO:3940),DVFTIDETTGK (SEQ ID NO:3941), EDETTK (SEQ ID NO:3942), EIDETTK (SEQ IDNO:3943), ETIDETTK (SEQ ID NO:3944), EFTIDETTK (SEQ ID NO:3945),DVFTIDETTK (SEQ ID NO:3946), EDETTGK (SEQ ID NO:3947), EIDETTGK (SEQ IDNO:3948), ETIDETTGK (SEQ ID NO:3949), EFTIDETTGK (SEQ ID NO:3950),EVFTIDETTGK (SEQ ID NO:3951), IDETT (SEQ ID NO:1778), TIDETT (SEQ IDNO:1779), DETTG (SEQ ID NO:1780), IDETTG (SEQ ID NO:1781) KDETE (SEQ IDNO:1782), KIDETE (SEQ ID NO:1783), KDETTE (SEQ ID NO:1784), KTIDETE (SEQID NO:1785), KIDETTE (SEQ ID NO:1786), KTIDETTE (SEQ ID NO:1787),KDETTGE (SEQ ID NO:1788), KIDETTGE (SEQ ID NO:1789), KTIDETTGE (SEQ IDNO:1790), KFTIDETE (SEQ ID NO:1791), KFTIDETTE (SEQ ID NO:1792),KFTIDETTGE (SEQ ID NO:1793), KVFTIDETE (SEQ ID NO:1794), KIFTIDETTE (SEQID NO:1795), KVFTIDETTGE (SEQ ID NO:1796), CDPKC (SEQ ID NO:1797),CDPKTC (SEQ ID NO:1798), CDPKTGC (SEQ ID NO:1799), CIDPKC (SEQ IDNO:1800), CIDPKTC (SEQ ID NO:1801), CIDPKTGC (SEQ ID NO:1802), CSIDPKC(SEQ ID NO:1803), CSIDPKTC (SEQ ID NO:1804), CSIDPKTGC (SEQ ID NO:1805),CFSIDPKC (SEQ ID NO:1806), CFSIDPKTC (SEQ ID NO:1807), CFSIDPKTGC (SEQID NO:1808), CYFSIDPKC (SEQ ID NO:1809), CYFSIDPKTC (SEQ ID NO:1810),CYFSIDPKTGC (SEQ ID NO:1811), EDPKK (SEQ ID NO:1812), EDPKTK (SEQ IDNO:1813), EDPKTGK (SEQ ID NO:1814), EIDPKK (SEQ ID NO:1815), EIDPKTK(SEQ ID NO:1816), EIDPKTGK (SEQ ID NO:1817), ESIDPKK (SEQ ID NO:1818),ESIDPKTK (SEQ ID NO:1819), ESIDPKTGK (SEQ ID NO:1820), EFSIDPKK (SEQ IDNO:1821), EFSIDPKTK (SEQ ID NO:1822), EFSIDPKTGK (SEQ ID NO:1823),EYFSIDPKK (SEQ ID NO:1824), EYFSIDPKTK (SEQ ID NO:1825), EYFSIDPKTGK(SEQ ID NO:1826), KDPKD (SEQ ID NO:1827), KDPKTD (SEQ ID NO:1828),KDPKTGD (SEQ ID NO:1829), KIDPKD (SEQ ID NO:1830), KIDPKTD (SEQ IDNO:1831), KIDPKTGD (SEQ ID NO:1832), KSIDPKD (SEQ ID NO:1833), KSIDPKTD(SEQ ID NO:1834), KSIDPKTGD (SEQ ID NO:1835), KFSIDPKD (SEQ ID NO:1836),KFSIDPKTD (SEQ ID NO:1837), KFSIDPKTGD (SEQ ID NO:1838), KYFSIDPKD (SEQID NO:1839), KYFSIDPKTD (SEQ ID NO:1840), KYFSIDPKTGD (SEQ ID NO:1841),DDPKK (SEQ ID NO:1842), DDPKTK (SEQ ID NO:1843), DDPKTGK (SEQ IDNO:1844), DIDPKK (SEQ ID NO:1845), DIDPKTK (SEQ ID NO:1846), DIDPKTGK(SEQ ID NO:1847), DSIDPKK (SEQ ID NO:1848), DSIDPKTK (SEQ ID NO:1849),DSIDPKTGK (SEQ ID NO:1850), DFSIDPKK (SEQ ID NO:1851), DFSIDPKTK (SEQ IDNO:1852), DFSIDPKTGK (SEQ ID NO:1853), DYFSIDPKK (SEQ ID NO:1854),DYFSIDPKTK (SEQ ID NO:1855), DYFSIDPKTGK (SEQ ID NO:1856), KDPKE (SEQ IDNO:1857), KDPKTE (SEQ ID NO:1858), KDPKTGE (SEQ ID NO:1859), KIDPKE (SEQID NO:1860), KIDPKTE (SEQ ID NO:1861), KIDPKTGE (SEQ ID NO:1862),KSIDPKE (SEQ ID NO:1863), KSIDPKTE (SEQ ID NO:1864), KSIDPKTGE (SEQ IDNO:1865), KFSIDPKE (SEQ ID NO:1866), KFSIDPKTE (SEQ ID NO:1867),KFSIDPKTGE (SEQ ID NO:1868), KYFSIDPKE (SEQ ID NO:1869), KYFSIDPKTE (SEQID NO:1870), KYFSIDPKTGE (SEQ ID NO:1871), DPKTG (SEQ ID NO:1872), IDPKT(SEQ ID NO:1873), IDPKTG (SEQ ID NO:1874), SIDPK (SEQ ID NO:1875),SIDPKT (SEQ ID NO:1876), SIDPKTG (SEQ ID NO:1877), FSIDPK (SEQ IDNO:1878), FSIDPKT (SEQ ID NO:1879), FSIDPKTG (SEQ ID NO:1880), YFSIDPK(SEQ ID NO:1881), YFSIDPKT (SEQ ID NO:1882) and YFSIDPKTG (SEQ IDNO:1883).
 49. A polynucleotide encoding a modulating agent according toclaim
 45. 50. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to acadherin-12 CAR sequence selected from the group consisting of VFTIDETTG(SEQ ID NO:266) and YFSIDPKTG (SEQ ID NO:280); and (b) modulates acadherin-12-mediated function.
 51. A modulating agent according to anyone of claims 1-4, wherein the agent comprises one or more cadherin-14CAR sequences selected from the group consisting DDT, IDDT (SEQ IDNO:281), DDTT (SEQ ID NO:282), IIDDT (SEQ ID NO:283), IDDTT (SEQ IDNO:284), IIDDTT (SEQ ID NO:285), DDTTG (SEQ ID NO:286), IDDTTG (SEQ IDNO:287), IIDDTTG (SEQ ID NO:288), FIIDDT (SEQ ID NO:289), FIIDDTT (SEQID NO:290), FIIDDTTG (SEQ ID NO:291), IFIIDDT (SEQ ID NO:292), IFIIDDTT(SEQ ID NO:293), IFIIDDTTG (SEQ ID NO:294), DPK, DPKT (SEQ ID NO:295),DPKTG (SEQ ID NO:296), VDPK (SEQ ID NO:297), VDPKT (SEQ ID NO:298),VDPKTG (SEQ ID NO:299), SVDPK (SEQ ID NO:300), SVDPKT (SEQ ID NO:301),SVDPKTG (SEQ ID NO:302), FSVDPK (SEQ ID NO:303), FSVDPKT (SEQ IDNO:304), FSVDPKTG (SEQ ID NO:305), YFSVDPK (SEQ ID NO:306), YFSVDPKT(SEQ ID NO:307), YFSVDPKTG (SEQ ID NO:308), DAN, DANT (SEQ ID NO:309),DANTG (SEQ ID NO:310), IDANT (SEQ ID NO:311), IDANTG (SEQ ID NO:312),NIDANT (SEQ ID NO:313), NIDANTG (SEQ ID NO:314), FNIDANT (SEQ IDNO:315), FNIDANTG (SEQ ID NO:316), FFNIDAN (SEQ ID NO:317), FFNIDANT(SEQ ID NO:318) and FFNIDANTG (SEQ ID NO:319).
 52. A modulating agentaccording to claim 51, wherein the agent comprises a linear peptidehaving the sequence N-Ac-IFIIDDTTG-NH₂ (SEQ ID NO:294),N-Ac-YFSVDPKTG-NH₂ (SEQ ID NO:308) or N-Ac-FFNIDANTG-NH₂ (SEQ IDNO:319).
 53. A modulating agent according to claim 51, wherein acadherin-14 CAR sequence is present within a cyclic peptide.
 54. Amodulating agent according to claim 53, wherein the cyclic peptidecomprises a sequence selected from the group consisting of CDDTC (SEQ IDNO:1884), CIDDTC (SEQ ID NO:1885), CDDTTC (SEQ ID NO:1886), CIIDDTC (SEQID NO:1887), CIDDTTC (SEQ ID NO:1888), CIIDDTTC (SEQ ID NO:1889),CDDTTGC (SEQ ID NO:1890), CIDDTTGC (SEQ ID NO:1891), CIIDDTTGC (SEQ IDNO:1892), CFIIDDTC (SEQ ID NO:1893), CFIIDDTTC (SEQ ID NO:1894),CFIIDDTTGC (SEQ ID NO:1895), CIFIIDDTC (SEQ ID NO:1896), CIFIIDDTTC (SEQID NO:1897), CIFIIDDTTGC (SEQ ID NO:1898), EDDTTK (SEQ ID NO:1899),EIDDTTK (SEQ ID NO:3952), EIIDDTTK (SEQ ID NO:3953), EFIIDDTTK (SEQ IDNO:3954), EIFIIDDTTK (SEQ ID NO:3955), EDDTTGK (SEQ ID NO:3956),EIDDTTGK (SEQ ID NO:3957), EIIDDTTGK (SEQ ID NO:3958), EFIIDDTTGK (SEQID NO:3959), EIFIIDDTTGK (SEQ ID NO:3960), DDDTTK (SEQ ID NO:3961),DIDDTTK (SEQ ID NO:3962), DFIIDDTTK (SEQ ID NO:3963), DIFIIDDTTK (SEQ IDNO:3964), DDDTTGK (SEQ ID NO:3965), DIDDTTGK (SEQ ID NO:3966), DIIDDTTGK(SEQ ID NO:3967), DFIIDDTTGK (SEQ ID NO:3968), DIFIIDDTTGK (SEQ IDNO:3969), DDDTK (SEQ ID NO:1900), DIDDTNK (SEQ ID NO:1901), DIIDDTK (SEQID NO:1902), DFIIDDTK (SEQ ID NO:1903), DIFIIDDTK (SEQ ID NO:1904),EDDTK (SEQ ID NO:1905), EIDDTK (SEQ ID NO:1906), EIIDDTK (SEQ IDNO:1907), EFIIDDTK (SEQ ID NO:1908), EIFIIDDTK (SEQ ID NO:1909), KDDTD(SEQ ID NO:1910), KIDDTD (SEQ ID NO:1911), KDDTTD (SEQ ID NO:1912),KIIDDTD (SEQ ID NO:1913), KIDDTTD (SEQ ID NO:1914), KIIDDTTD (SEQ IDNO:1915), KDDTTGD (SEQ ID NO:1916), KIDDTTGD (SEQ ID NO:1917), KIIDDTTGD(SEQ ID NO:1918), KFIIDDTD (SEQ ID NO:1919), KFIIDDTTD (SEQ ID NO:1920),KFIIDDTTGD (SEQ ID NO:1921), KIFIIDDTD (SEQ ID NO:1922), KIFIIDDTTD (SEQID NO:1923), KIFIIDDTTGD (SEQ ID NO:1924), DDTT (SEQ ID NO:1925), IDDTT(SEQ ID NO:1926), IIDDTT (SEQ ID NO:1927), DDTTG (SEQ ID NO:1928),IDDTTG (SEQ ID NO:1929) KDDTE (SEQ ID NO:1930), KIDDTE (SEQ ID NO:1931),KDDTTE (SEQ ID NO:1932), KIIDDTE (SEQ ID NO:1933), KIDDTTE (SEQ IDNO:1934), KIIDDTTE (SEQ ID NO:1935), KDDTTGE (SEQ ID NO:1936), KIDDTTGE(SEQ ID NO:1937), KIIDDTTGE (SEQ ID NO:1938), KFIIDDTE (SEQ ID NO:1939),KFIIDDTTE (SEQ ID NO:1940), KFIIDDTTGE (SEQ ID NO:1941), KIFIIDDTE (SEQID NO:1942), KIFIIDDTTE (SEQ ID NO:1943), KIFIIDDTTGE (SEQ ID NO:1944),CDPKC (SEQ ID NO:1945), CVDPKC (SEQ ID NO:1946), CVDPKTC (SEQ IDNO:1947), CVDPKTGC (SEQ ID NO:1948), CSVDPKC (SEQ ID NO:1949), CSVDPKTC(SEQ ID NO:1950), CSVDPKTGC (SEQ ID NO:1951), CFSVDPKC (SEQ ID NO:1952),CFSVDPKTC (SEQ ID NO:1953), CFSVDPKTGC (SEQ ID NO:1954), CYFSVDPKC (SEQID NO:1955), CYFSVDPKTC (SEQ ID NO:1956), CYFSVDPKTGC (SEQ ID NO:1957),CDPKTC (SEQ ID NO:3970), CDPKTGC (SEQ ID NO:3971), CDANC (SEQ IDNO:1958), CDANTC (SEQ ID NO:1959), CDANTGC (SEQ ID NO:1960), CIDANTC(SEQ ID NO:1961), CIDANTGC (SEQ ID NO:1962), CNIDANTC (SEQ ID NO:1963),CNIDANTGC (SEQ ID NO:1964), CFNIDANTC (SEQ ID NO:1965), CFNIDANTGC (SEQID NO:1966), CFFNIDANC (SEQ ID NO:1967), CFFNIDANTC (SEQ ID NO:1968),CFFNIDANTGC (SEQ ID NO:1969), CIDANC (SEQ ID NO:3972), CNIDANC (SEQ IDNO:3973), CFNIDANC (SEQ ID NO:3974), EDPKK (SEQ ID NO:1970), EDPKTK (SEQID NO:1971), EDPKTGK (SEQ ID NO:1972), EVDPKK (SEQ ID NO:1973), EVDPKTK(SEQ ID NO:1974), EVDPKTGK (SEQ ID NO:1975), ESVDPKK (SEQ ID NO:1976),ESVDPKTK (SEQ ID NO:1977), ESVDPKTGK (SEQ ID NO:1978), EFSVDPKK (SEQ IDNO:1979), EFSVDPKTK (SEQ ID NO:1980), EFSVDPKTGK (SEQ ID NO:1981),EYFSVDPKK (SEQ ID NO: 1982), EYFSVDPKTK (SEQ ID NO:1983), EYFSVDPKTGK(SEQ ID NO:1984), EDANK (SEQ ID NO:1985), EDANTK (SEQ ID NO:1986),EDANTGK (SEQ ID NO:1987), EIDANTK (SEQ ID NO:1988), EIDANTGK (SEQ IDNO:1989), ENIDANTK (SEQ ID NO:1990), ENIDANTGK (SEQ ID NO:1991),EFNIDANTK (SEQ ID NO:1992), EFNIDANTGK (SEQ ID NO:1993), EFFNIDANK (SEQID NO:1994), EFFNIDANTK (SEQ ID NO:1995), EFFNIDANTGK (SEQ ID NO:1996),EIDANK (SEQ ID NO:3975), ENIDANK (SEQ ID NO:3976), EFNIDANK (SEQ IDNO:3977), KVDPKD (SEQ ID NO:1997), KVDPKTD (SEQ ID NO:1998), KVDPKTGD(SEQ ID NO:1999), KSVDPKD (SEQ ID NO:2000), KSVDPKTD (SEQ ID NO:2001),KSVDPKTGD (SEQ ID NO:2002), KFSVDPKD (SEQ ID NO:2003), KFSVDPKTD (SEQ IDNO:2004), KFSVDPKTGD (SEQ ID NO:2005), KYFSVDPKD (SEQ ID NO:2006),KYFSVDPKTD (SEQ ID NO:2007), KYFSVDPKTGD (SEQ ID NO:2008), KDPKD (SEQ IDNO:3978), KDPKTD (SEQ ID NO:3979), KDPKTGD (SEQ ID NO:3980), KDAND (SEQID NO:3981), KIDAND (SEQ ID NO:3982), KNIDAND (SEQ ID NO:3983), KDANTD(SEQ ID NO:2009), KDANTGD (SEQ ID NO:2010), KIDANTD (SEQ ID NO:2011),KIDANTGD (SEQ ID NO:2012), KNIDANTD (SEQ ID NO:2013), KNIDANTGD (SEQ IDNO:2014), KFNIDANTD (SEQ ID NO:2015), KFNIDANTGD (SEQ ID NO:2016),KFFNIDAND (SEQ ID NO:2017), KFFNIDANTD (SEQ ID NO:2018), KFFNIDANTGD(SEQ ID NO:2019), DDPKK (SEQ ID NO:2020), DDPKTK (SEQ ID NO:2021),DDPKTGK (SEQ ID NO:2022), DVDPKK (SEQ ID NO:2023), DVDPKTK (SEQ IDNO:2024), DVDPKTGK (SEQ ID NO:2025), DSVDPKK (SEQ ID NO:2026), DSVDPKTK(SEQ ID NO:2027), DSVDPKTGK (SEQ ID NO:2028), DFSVDPKK (SEQ ID NO:2029),DFSVDPKTK (SEQ ID NO:2030), DFSVDPKTGK (SEQ ID NO:2031), DYFSVDPKK (SEQID NO:2032), DYFSVDPKTK (SEQ ID NO:2033), DYFSVDPKTGK (SEQ ID NO:2034),DDANK (SEQ ID NO:2035), DDANTK (SEQ ID NO:2036), DDANTGK (SEQ IDNO:2037), DIDANTK (SEQ ID NO:2038), DIDANTGK (SEQ ID NO:2039), DNIDANTK(SEQ ID NO:2040), DNIDANTGK (SEQ ID NO:2041), DFNIDANTC (SEQ IDNO:2042), DFNIDANTGK (SEQ ID NO:2043), DFFNIDANK (SEQ ID NO:2044),DFFNIDANTK (SEQ ID NO:2045), DFFNIDANTGK (SEQ ID NO:2046), DIDANK (SEQID NO:3984), DNIDANK (SEQ ID NO:3985), DFNIDANK (SEQ ID NO:3986),DFNIDANTK (SEQ ID NO:3987), KDPKE (SEQ ID NO:3988), KDPKTE (SEQ IDNO:3989), KDPKTGE (SEQ ID NO:3990), KVDPKE (SEQ ID NO:2047), KVDPKTE(SEQ ID NO:2048), KVDPKTGE (SEQ ID NO:2049), KSVDPKE (SEQ ID NO:2050),KSVDPKTE (SEQ ID NO:2051), KSVDPKTGE (SEQ ID NO:2052), KFSVDPKE (SEQ IDNO:2053), KFSVDPKTE (SEQ ID NO:2054), KFSVDPKTGE (SEQ ID NO:2055),KYFSVDPKE (SEQ ID NO:2056), KYFSVDPKTE (SEQ ID NO:2057), KYFSVDPKTGE(SEQ ID NO:2058), KDANE (SEQ ID NO:2059), KDANTE (SEQ ID NO:2060),KDANTGE (SEQ ID NO:2061), KIDANTE (SEQ ID NO:2062), KIDANTGE (SEQ IDNO:2063), KNIDANTE (SEQ ID NO:2064), KNIDANTGE (SEQ ID NO:2065),KFNIDANTE (SEQ ID NO:2066), KFNIDANTGE (SEQ ID NO:2067), KFFNIDANE (SEQID NO:2068), KFFNIDANTE (SEQ ID NO:2069), KFFNIDANTGE (SEQ ID NO:2070),KIDANE (SEQ ID NO:3991), KNIDANE (SEQ ID NO:3992), KFNIDANE (SEQ IDNO:3993), VDPKT (SEQ ID NO:2071), VDPKTG (SEQ ID NO:2072), SVDPK (SEQ IDNO:2073), SVDPKT (SEQ ID NO:2074), SVDPKTG (SEQ ID NO:2075), FSVDPK (SEQID NO:2076), FSVDPKT (SEQ ID NO:2077), FSVDPKTG (SEQ ID NO:2078),YFSVDPK (SEQ ID NO:2079), YFSVDPKT (SEQ ID NO:2080), YFSVDPKTG (SEQ IDNO:2081), DANTG (SEQ ID NO:2082), IDANT (SEQ ID NO:2083), IDANTG (SEQ IDNO:2084), NIDANT (SEQ ID NO:2085), NIDANTG (SEQ ID NO:2086), FNIDANT(SEQ ID NO:2087), FNIDANTG (SEQ ID NO:2088), FFNIDAN (SEQ ID NO:2089),FFNIDANT (SEQ ID NO:2090), and FFNIDANTG (SEQ ID NO:2091).
 55. Apolynucleotide encoding a modulating agent according to claim
 51. 56. Amodulating agent comprising an antibody or antigen-binding fragmentthereof that: (a) specifically binds to a cadherin-14 CAR sequenceselected from the group consisting of IFIIDDTTG (SEQ ID NO:294),YFSVDPKTG (SEQ ID NO:308) and FFNIDANTG (SEQ ID NO:319), and (b)modulates a cadherin-14-mediated function.
 57. A modulating agentaccording to any one of claims 1-4, wherein the agent comprises one ormore cadherin-15 CAR sequences selected from the group consisting ofDKF, IDKF (SEQ ID NO:320), DKFT (SEQ ID NO:321), SIDKF (SEQ ID NO:322),IDKFT (SEQ ID NO:323), SIDKFT (SEQ ID NO:324), DKFTG (SEQ ID NO:325),IDKFTG (SEQ ID NO:326), SIDKFTG (SEQ ID NO:327), FSIDKF (SEQ ID NO:328),FSIDKFT (SEQ ID NO:329), FSIDKFTG (SEQ ID NO:330), VFSIDKF (SEQ IDNO:331), VFSIDKFT (SEQ ID NO:332), VFSIDKFTG (SEQ ID NO:333), DEL, DELT(SEQ ID NO:334), DELTG (SEQ ID NO:335), IDEL (SEQ ID NO:336), IDELT (SEQID NO:337), IDELTG (SEQ ID NO:338), SIDEL (SEQ ID NO:339), SIDELT (SEQID NO:340), SIDELTG (SEQ ID NO:341), FSIDEL (SEQ ID NO:342), FSIDELT(SEQ ID NO:343), FSIDELTG (SEQ ID NO:344), LFSIDEL (SEQ ID NO:345),LFSIDELT (SEQ ID NO:346) and LFSIDELTG (SEQ ID NO:347).
 58. A modulatingagent according to claim 57, wherein the agent comprises a linearpeptide having the sequence N-Ac-VFSIDKFTG-NH₂ (SEQ ID NO:333) orN-Ac-LFSIDELTG-NH₂ (SEQ ID NO:347).
 59. A modulating agent according toclaim 57, wherein a cadherin-15 CAR sequence is present within a cyclicpeptide.
 60. A modulating agent according to claim 59, wherein thecyclic peptide comprises a sequence selected from the group consistingof CDKFC (SEQ ID NO:2092), CIDKFC (SEQ ID NO:2093), CDKFTC (SEQ IDNO:2094), CSIDKFC (SEQ ID NO:2095), CIDKFTC (SEQ ID NO:2096), CSIDKFTC(SEQ ID NO:2097), CDKFTGC (SEQ ID NO:2098), CIDKFTGC (SEQ ID NO:2099),CSIDKFTGC (SEQ ID NO:2100), CFSIDKFC (SEQ ID NO:2101), CFSIDKFTC (SEQ IDNO:2102), CFSIDKFTGC (SEQ ID NO:2103), CVFSIDKFC (SEQ ID NO:2104),CVFSIDKFTC (SEQ ID NO:2105), CVFSIDKFTGC (SEQ ID NO:2106), DDKFK (SEQ IDNO:2108), DIDKFK (SEQ ID NO:2109), DSIDKFK (SEQ ID NO:2110), DFSIDKFK(SEQ ID NO:2111), DVFSIDKFK (SEQ ID NO:2112), DDKFTK (SEQ ID NO:2107),DIDKFTK (SEQ ID NO:2133), DSIDKFTK (SEQ ID NO:3994), DFSIDKFTK (SEQ IDNO:3995), DVFSIDKFTK (SEQ ID NO:3996), DDKTGK (SEQ ID NO:3997), DIDKFTGK(SEQ ID NO:3998), DSIDKFTGK (SEQ ID NO:3999), DFSIDKFTGK (SEQ IDNO:4000), DVFSIDKFTGK (SEQ ID NO:4001), EDKFTK (SEQ ID NO:4002), EIDKFTK(SEQ ID NO:4003), ESIDKFTK (SEQ ID NO:4004), EFSIDKFTK (SEQ ID NO:4005),EVFSIDKFTK (SEQ ID NO:4006), EDKFTGK (SEQ ID NO:4007), EIDKFTGK (SEQ IDNO:4008), EFSIDKFTGK (SEQ ID NO:4009), EVFSIDKFTGK (SEQ ID NO:4010),EDKFK (SEQ ID NO:2113), EIDKFK (SEQ ID NO:2114), ESIDKFK (SEQ IDNO:2115), EFSIDKFK (SEQ ID NO:2116), EVFSIDKFK (SEQ ID NO:2117), KDKFD(SEQ ID NO:2118), KIDKFD (SEQ ID NO:2119), KDKFTD (SEQ ID NO:2120),KSIDKFD (SEQ ID NO:2121), KIDKFTD (SEQ ID NO:2122), KSIDKFTD (SEQ IDNO:2123), KDKFTGD (SEQ ID NO:2124), KIDKFTGD (SEQ ID NO:2125), KSIDKFTGD(SEQ ID NO:2126), KFSIDKFD (SEQ ID NO:2127), KFSIDKFTD (SEQ ID NO:2128),KFSIDKFTGD (SEQ ID NO:2129), KVFSIDKFD (SEQ ID NO:2130), KVFSIDKFTD (SEQID NO:2131), KVFSIDKFTGD (SEQ ID NO:2132), IDKFT (SEQ ID NO:2134),SIDKFT (SEQ ID NO:2135), DKFTG (SEQ ID NO:2136), IDKFTG (SEQ ID NO:2137)KDKFE (SEQ ID NO:2138), KIDKFE (SEQ ID NO:2139), KDKFTE (SEQ IDNO:2140), KSIDKFE (SEQ ID NO:2141), KIDKFTE (SEQ ID NO:2142), KSIDKFTE(SEQ ID NO:2143), KDKFTGE (SEQ ID NO:2144), KIDKFTGE (SEQ ID NO:2145),KSIDKFTGE (SEQ ID NO:2146), KFSIDKFE (SEQ ID NO:2147), KFSIDKFTE (SEQ IDNO:2148), KFSIDKFTGE (SEQ ID NO:2149), KVFSIDKFE (SEQ ID NO:2150),KIFSIDKFTE (SEQ ID NO:2151), KVFSIDKFTGE (SEQ ID NO:2152), CDELC (SEQ IDNO:2153), CDELTC (SEQ ID NO:2154), CDELTGC (SEQ ID NO:2155), CIDELC (SEQID NO:2156), CIDELTC (SEQ ID NO:2157), CIDELTGC (SEQ ID NO:2158),CSIDELC (SEQ ID NO:2159), CSIDELTC (SEQ ID NO:2160), CSIDELTGC (SEQ IDNO:2161), CFSIDELC (SEQ ID NO:2162), CFSIDELTC (SEQ ID NO:2163),CFSIDELTGC (SEQ ID NO:2164), CLFSIDELC (SEQ ID NO:2165), CLFSIDELTC (SEQID NO:2166), CLFSIDELTGC (SEQ ID NO:2167), EDELCK (SEQ ID NO:2168),EDELTK (SEQ ID NO:2169), EDELTGK (SEQ ID NO:2170), EIDELK (SEQ IDNO:2171), EIDELTK (SEQ ID NO:2172), EIDELTGK (SEQ ID NO:2173), ESIDELK(SEQ ID NO:2174), ESIDELTK (SEQ ID NO:2175), ESIDELTGK (SEQ ID NO:2176),EFSIDELK (SEQ ID NO:2177), EFSIDELTK (SEQ ID NO:2178), EFSIDELTGK (SEQID NO:2179), ELFSIDELK (SEQ ID NO:2180), ELFSIDELTK (SEQ ID NO:2181),ELFSIDELTGK (SEQ ID NO:2182), KDELD (SEQ ID NO:2183), KDELTD (SEQ IDNO:2184), KDELTGD (SEQ ID NO:2185), KIDELD (SEQ ID NO:2186), KIDELTD(SEQ ID NO:2187), KIDELTGD (SEQ ID NO:2188), KSIDELD (SEQ ID NO:2189),KSIDELTD (SEQ ID NO:2190), KSIDELTGD (SEQ ID NO:2191), KFSIDELD (SEQ IDNO:2192), KFSIDELTD (SEQ ID NO:2193), KFSIDELTGD (SEQ ID NO:2194),KLFSIDELD (SEQ ID NO:2195), KLFSIDELTD (SEQ ID NO:2196), KLFSIDELTGD(SEQ ID NO:2197), DDELK (SEQ ID NO:2198), DDELTK (SEQ ID NO:2199),DDELTGK (SEQ ID NO:2200), DIDELK (SEQ ID NO:2201), DIDELTK (SEQ IDNO:2202), DIDELTGK (SEQ ID NO:2203), DSIDELK (SEQ ID NO:2204), DSIDELTK(SEQ ID NO:2205), DSIDELTGK (SEQ ID NO:2206), DFSIDELK (SEQ ID NO:2207),DFSIDELTK (SEQ ID NO:2208), DFSIDELTGK (SEQ ID NO:2209), DLFSIDELK (SEQID NO:2210), DLFSIDELTK (SEQ ID NO:2211), DLFSIDELTGK (SEQ ID NO:2212),KDELE (SEQ ID NO:2213), KDELTE (SEQ ID NO:2214), KDELTGE (SEQ IDNO:2215), KIDELE (SEQ ID NO:2216), KIDELTE (SEQ ID NO:2217), KIDELTGE(SEQ ID NO:2218), KSIDELE (SEQ ID NO:2219), KSIDELTE (SEQ ID NO:2220),KSIDELTGE (SEQ ID NO:2221), KFSIDELE (SEQ ID NO:2222), KFSIDELTE (SEQ IDNO:2223), KFSIDELTGE (SEQ ID NO:2224), KLFSIDELE (SEQ ID NO:2225),KLFSIDELTE (SEQ ID NO:2226), KLFSIDELTGE (SEQ ID NO:2227), DELTG (SEQ IDNO:2228), IDELT (SEQ ID NO:2229), IDELTG (SEQ ID NO:2230), SIDEL (SEQ IDNO:2231), SIDELT (SEQ ID NO:2232), SIDELTG (SEQ ID NO:2233), FSIDEL (SEQID NO:2234), FSIDELT (SEQ ID NO:2235), FSIDELTG (SEQ ID NO:2236),LFSIDEL (SEQ ID NO:2237), LFSIDELT (SEQ ID NO:2238) and LFSIDELTG. (SEQID NO:2239).
 61. A polynucleotide encoding a modulating agent accordingto claim
 57. 62. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to acadherin-15 CAR sequence selected from the group consisting of VFSIDKFTG(SEQ ID NO:333) and LFSIDELTG (SEQ ID NO:347); and (b) modulates acadherin-15-mediated function.
 63. A modulating agent according to anyone of claims 1-4, wherein the agent comprises one or more T-cadherinCAR sequences selected from the group consisting of NEN, INEN (SEQ IDNO:348), NENT (SEQ ID NO:349), RINEN (SEQ ID NO:350), INENT (SEQ IDNO:351), RINENT (SEQ ID NO:352), NENTG (SEQ ID NO:353), INENTG (SEQ IDNO:354), RINENTG (SEQ ID NO:355), FRINEN (SEQ ID NO:356), FRINENT (SEQID NO:357), FRINENTG (SEQ ID NO:358), IFRINEN (SEQ ID NO:359), IFRINENT(SEQ ID NO:360) and IFRINENTG (SEQ ID NO:361).
 64. A modulating agentaccording to claim 63, wherein the agent comprises a linear peptidehaving the sequence N-Ac-IFRINENTG-NH₂ (SEQ ID NO:361).
 65. A modulatingagent according to claim 63, wherein a T-cadherin CAR sequence ispresent within a cyclic peptide.
 66. A modulating agent according toclaim 65, wherein the cyclic peptide comprises a sequence selected fromthe group consisting of CNENC (SEQ ID NO:2240), CINENC (SEQ ID NO:2241),CNENTC (SEQ ID NO:2242), CRINENC (SEQ ID NO:2243), CINENTC (SEQ IDNO:2244), CRINENTC (SEQ ID NO:2245), CNENTGC (SEQ ID NO:2246), CINENTGC(SEQ ID NO:2247), CRINENTGC (SEQ ID NO:2248), CFRINENC (SEQ ID NO:2249),CFRINENTC (SEQ ID NO:2250), CFRINENTGC (SEQ ID NO:2251), CIFRINENC (SEQID NO:2252), CIFRINENTC (SEQ ID NO:2253), CIFRINENTGC (SEQ ID NO:2254),DNENK (SEQ ID NO:2255), DINENK (SEQ ID NO:2256), DRINENK (SEQ IDNO:2257), DFRINENK (SEQ ID NO:2258), DIFRINENK (SEQ ID NO:2259), ENENK(SEQ ID NO:2260), EINENK (SEQ ID NO:2261), ERINENK (SEQ ID NO:2262),EFRINENK (SEQ ID NO:2263), EIFRINENK (SEQ ID NO:2264), KNEND (SEQ IDNO:2265), KINEND (SEQ ID NO:2266), KNENTD (SEQ ID NO:2267), KRINEND (SEQID NO:2268), KINENTD (SEQ ID NO:2269), KRINENTD (SEQ ID NO:2270),KNENTGD (SEQ ID NO:2271), KINENTGD (SEQ ID NO:2272), KRINENTGD (SEQ IDNO:2273), KFRINEND (SEQ ID NO:2274), KFRINENTD (SEQ ID NO:2275),KFRINENTGD (SEQ ID NO:2276), KIFRINEND (SEQ ID NO:2277), KIFRINENTD (SEQID NO:2278), KIFRINENTGD (SEQ ID NO:2279), DNENTK (SEQ ID NO:4011),DINENTK (SEQ ID NO:4012), DRINENTK (SEQ ID NO:4013), DFRINENTK (SEQ IDNO:4014), DIFRINENTK (SEQ ID NO:4015), DNENTGK (SEQ ID NO:4016),DINENTGK (SEQ ID NO:4017), DRINENTGK (SEQ ID NO:4018), DFRINENTGK (SEQID NO:4019), DIFRINENTGK (SEQ ID NO:4020), ENENTK (SEQ ID NO:4021),EINENTK (SEQ ID NO:4022), ERINENTK (SEQ ID NO:4023), EFRINENTK (SEQ IDNO:4024), EIFRINENTK (SEQ ID NO:4025), ENENTGK (SEQ ID NO:4026),EINENTGK (SEQ ID NO:4027), ERINENTGK (SEQ ID NO:4028), EFRINENTGK (SEQID NO:4029), EIFRINENTGK (SEQ ID NO:4030), VNENTG (SEQ ID NO:4031),RINENTG (SEQ ID NO:4032), FRINEN (SEQ ID NO:4033), FRINENT (SEQ IDNO:4034), FRINENTG (SEQ ID NO:4035), IFRINEN (SEQ ID NO:4036), IFRINENT(SEQ ID NO:4037), IFRINENTG (SEQ ID NO:4038), VNENT (SEQ ID NO:2280),INENT (SEQ ID NO:2281), RINENT (SEQ ID NO:2282), NENTG (SEQ ID NO:2283),INENTG (SEQ ID NO:2284) KNENE (SEQ ID NO:2285), KINENE (SEQ ID NO:2286),KNENTE (SEQ ID NO:2287), KRINENE (SEQ ID NO:2288), KINENTE (SEQ IDNO:2289), KRINENTE (SEQ ID NO:2290), KNENTGE (SEQ ID NO:2291), KINENTGE(SEQ ID NO:2292), KRINENTGE (SEQ ID NO:2293), KFRINENE (SEQ ID NO:2294),KFRINENTE (SEQ ID NO:2295), KFRINENTGE (SEQ ID NO:2296), KIFRINENE (SEQID NO:2297), KIFRINENTE (SEQ ID NO:2298) and KIFRINENTGE (SEQ IDNO:2299).
 67. A polynucleotide encoding a modulating agent according toclaim
 63. 68. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to theT-cadherin CAR sequence IFRINENTG (SEQ ID NO:361); and (b) modulates aT-cadherin-mediated function.
 69. A modulating agent according to anyone of claims 1-4, wherein the agent comprises one or more PB-cadherinCAR sequences selected from the group consisting of EEY, EEYT (SEQ IDNO:362), EEYTG (SEQ ID NO:363), VEEY (SEQ ID NO:364), VEEYT (SEQ IDNO:365), VEEYTG (SEQ ID NO:366), VVEEY (SEQ ID NO:367), VVEEYT (SEQ IDNO:368), VVEEYTG (SEQ ID NO:369), FVVEEY (SEQ ID NO:370), FVEEYT (SEQ IDNO:371), FVEEYTG (SEQ ID NO:372), FFVVEEY (SEQ ID NO:373), FFVVEEYT (SEQID NO:374), FFVVEEYTG (SEQ ID NO:375), DEL, DELT (SEQ ID NO:376), DELTG(SEQ ID NO:377), IDEL (SEQ ID NO:378), IDELT (SEQ ID NO:379), IDELTG(SEQ ID NO:380), LIDEL (SEQ ID NO:381), LIDELT (SEQ ID NO:382), LIDELTG(SEQ ID NO:383), FLIDEL (SEQ ID NO:384), FLIDELT (SEQ ID NO:385),FLIDELTG (SEQ ID NO:386), IFLIDEL (SEQ ID NO:387), IFLIDELT (SEQ IDNO:388), IFLIDELTG (SEQ ID NO:389), DPK, DPKT (SEQ ID NO:390), DPKTG(SEQ ID NO:391), VDPK (SEQ ID NO:392), VDPKT (SEQ ID NO:393), VDPKTG(SEQ ID NO:394), TVDPK (SEQ ID NO:395), TVDPKT (SEQ ID NO:396), TVDPKTG(SEQ ID NO:397), FTVDPK (SEQ ID NO:398), FTVDPKT (SEQ ID NO:399),FTVDPKTG (SEQ ID NO:400), HFTVDPK (SEQ ID NO:401), HFTVDPKT (SEQ IDNO:402), HFTVDPKTG (SEQ ID NO:403), DAD, DADT (SEQ ID NO:404), DADTG(SEQ ID NO:405), IDAD (SEQ ID NO:406), IDADT (SEQ ID NO:407), IDADTG(SEQ ID NO:408), DIDAD (SEQ ID NO:409), DIDADT (SEQ ID NO:410), DIDADTG(SEQ ID NO:411), FDIDAD (SEQ ID NO:412), FDIDADT (SEQ ID NO:413),FDIDADTG (SEQ ID NO:414), IFDIDAD (SEQ ID NO:415), IFDIDADT (SEQ IDNO:416) and IFDIDADTG (SEQ ID NO:417);
 70. A modulating agent accordingto claim 69, wherein the agent comprises a linear peptide having thesequence N-Ac-FFVVEEYTG-NH₂ (SEQ ID NO1:375), N-Ac-IFLIDELTG-NH₂ (SEQ IDNO:389), N-Ac-HFTVDPKTG-NH₂ (SEQ ID NO:403) or N-Ac-IFDIDADTG-NH₂ (SEQID NO:417).
 71. A modulating agent according to claim 69, wherein aPB-cadherin CAR sequence is present within a cyclic peptide.
 72. Amodulating agent according to claim 71, wherein the cyclic peptidecomprises a sequence selected from the group consisting of CEEYC (SEQ IDNO:2300), CEEYTC (SEQ ID NO:2301), CEEYTG (SEQ ID NO:2302), CVEEYC (SEQID NO:2303), CVEEYTC (SEQ ID NO:2304), CVEEYTGC (SEQ ID NO:2305),CVVEEYC (SEQ ID NO:2306), CVVEEYTC (SEQ ID NO:2307), CVVEEYTGC (SEQ IDNO:2308), CFVVEEYC (SEQ ID NO:2309), CFVEEYTC (SEQ ID NO:2310),CFVEEYTGC (SEQ ID NO:2311), CFFVVEEYC (SEQ ID NO:2312), CFFVVEEYT° C.(SEQ ID NO:2313), CFFVVEEYTGC (SEQ ID NO:2314), CLIDELC (SEQ IDNO:2315), CLIDELTC (SEQ ID NO:2316), CLIDELTGC (SEQ ID NO:2317),CFLIDELC (SEQ ID NO:2318), CFLIDELTC (SEQ ID NO:2319), CFLIDELTGC (SEQID NO:2320), CIFLIDELC (SEQ ID NO:2321), CIFLIDELTC (SEQ ID NO:2322),CIFLIDELTGC (SEQ ID NO:2323), CDELC (SEQ ID NO:4039), CDELTC (SEQ IDNO:4040), CDELTGC (SEQ ID NO:4041), CIDELC (SEQ ID NO:4042), CIDELTC(SEQ ID NO:4043), CIDELTGC (SEQ ID NO:4044), CDPKC (SEQ ID NO:4045),CDPKTC (SEQ ID NO:4046), CDPKTGC (SEQ ID NO:4047), CVDPKC (SEQ IDNO:4048), CVDPKTC (SEQ ID NO:4049), CVDPKTGC (SEQ ID NO:4050), CTVDPKC(SEQ ID NO:2324), CTVDPKTC (SEQ ID NO:2325), CTVDPKTGC (SEQ ID NO:2326),CFTVDPKC (SEQ ID NO:2327), CFTVDPKTC (SEQ ID NO:2328), CFTVDPKTGC (SEQID NO:2329), CHFTVDPKC (SEQ ID NO:2330), CHFTVDPKTC (SEQ ID NO:2331),CHFTVDPKTGC (SEQ ID NO:2332), CDADC (SEQ ID NO:2333), CDADTC (SEQ IDNO:2334), CDADTGC (SEQ ID NO:2335), CIDADC (SEQ ID NO:2336), CIDADTC(SEQ ID NO:2337), CIDADTGC (SEQ ID NO:2338), CDIDADC (SEQ ID NO:2339),CDIDADTC (SEQ ID NO:2340), CDIDADTGC (SEQ ID NO:2341), CFDIDADC (SEQ IDNO:2342), CFDIDADTC (SEQ ID NO:2343), CFDIDADTGC (SEQ ID NO:2344),CIFDIDADC (SEQ ID NO:2345), CIFDIDADTC (SEQ ID NO:2346), CIFDIDADTGC(SEQ ID NO:2347), EEEYK (SEQ ID NO:2348), EEEYTK (SEQ ID NO:2349),EEEYTGK (SEQ ID NO:2350), EVEEYK (SEQ ID NO:2351), EVEEYTK (SEQ IDNO:2352), EVEEYTGK (SEQ ID NO:235.3), EVVEEYK (SEQ ID NO:2354), EVVEEYTK(SEQ ID NO:2355), EVVEEYTGK (SEQ ID NO:2356), EFVVEEYK (SEQ ID NO:2357),EFVEEYTK (SEQ ID NO:2358), EFVEEYTGK (SEQ ID NO:2359), EFFVVEEYK (SEQ IDNO:2360), EFFVVEEYTK (SEQ ID NO:2361), EFFVVEEYTGK (SEQ ID NO:2362),EDELK (SEQ ID NO:2363), EDELTK (SEQ ID NO:2364), EDELTGK (SEQ IDNO:2365), EIDELK (SEQ ID NO:2366), EIDELTK (SEQ ID NO:2367), EIDELTGK(SEQ ID NO:2368), ELIDELK (SEQ ID NO:2369), ELIDELTK (SEQ ID NO:2370),ELIDELTGK (SEQ ID NO:2371), EFLIDELK (SEQ ID NO:2372), EFLIDELTK (SEQ IDNO:2373), EFLIDELTGK (SEQ ID NO:2374), EIFLIDELK (SEQ ID NO:2375),EIFLIDELTK (SEQ ID NO:2376), EIFLIDELTGK (SEQ ID NO:2377), EDPKK (SEQ IDNO:2378), EDPKTK (SEQ ID NO:2379), EDPKTGK (SEQ ID NO:2380), EVDPKK (SEQID NO:2381), EVDPKTK (SEQ ID NO:2382), EVDPKTGK (SEQ ID NO:2383),ETVDPKK (SEQ ID NO:2384), ETVDPKTK (SEQ ID NO:2385), ETVDPKTGK (SEQ IDNO:2386), EFTVDPKK (SEQ ID NO:2387), EFTVDPKTK (SEQ ID NO:2388),EFTVDPKTGK (SEQ ID NO:2389), EHFTVDPKK (SEQ ID NO:2390), EHFTVDPKTK (SEQID NO:2391), EHFTVDPKTGK (SEQ ID NO:2392), EDADK (SEQ ID NO:2393),EDADTK (SEQ ID NO:2394), EDADTGK (SEQ ID NO:2395), EIDADK (SEQ IDNO:2396), EIDADTK (SEQ ID NO:2397), EIDADTGK (SEQ ID NO:2398), EDIDADK(SEQ ID NO:2399), EDIDADTK (SEQ ID NO:2400), EDIDADTGK (SEQ ID NO:2401),EFDIDADK (SEQ ID NO:2402), EFDIDADTK (SEQ ID NO:2403), EFDIDADTGK (SEQID NO:2404), EIFDIDADK (SEQ ID NO:2405), EIFDIDADTK (SEQ ID NO:2406),EIFDIDADTGK (SEQ ID NO:2407), KEEYD (SEQ ID NO:2408), KEEYTD (SEQ IDNO:2409), KEEYTGD (SEQ ID NO:2410), KVEEYD (SEQ ID NO:2411), KVEEYTD(SEQ ID NO:2412), KVEEYTGD (SEQ ID NO:2413), KVVEEYD (SEQ ID NO:2414),KVVEEYTD (SEQ ID NO:2415), KVVEEYTGD (SEQ ID NO:2416), KFVVEEYD (SEQ IDNO:2417), KFVEEYTD (SEQ ID NO:2418), KFVEEYTGD (SEQ ID NO:2419),KFFVVEEYD (SEQ ID NO:2420), KFFVVEEYTD (SEQ ID NO:2421), KFFVVEEYTGD(SEQ ID NO:2422), KDELD (SEQ ID NO:2423), KDELTD (SEQ ID NO:2424),KDELTGD (SEQ ID NO:2425), KIDELD (SEQ ID NO:2426), KIDELTD (SEQ IDNO:2427), KIDELTGD (SEQ ID NO:2428), KLIDELD (SEQ ID NO:2429), KLIDELTD(SEQ ID NO:2430), KLIDELTGD (SEQ ID NO:2431), KFLIDELD (SEQ ID NO:2432),KFLIDELTD (SEQ ID NO:2433), KFLIDELTGD (SEQ ID NO:2434), KIFLIDELD (SEQID NO:2435), KIFLIDELTD (SEQ ID NO:2436), KIFLIDELTGD (SEQ ID NO:2437),KDPKD (SEQ ID NO:2438), KDPKTD (SEQ ID NO:2439), KDPKTGD (SEQ IDNO:2440), KVDPKD (SEQ ID NO:2441), KVDPKTD (SEQ ID NO:2442), KVDPKTGD(SEQ ID NO:2443), KTVDPKD (SEQ ID NO:2444), KTVDPKTD (SEQ ID NO:2445),KTVDPKTGD (SEQ ID NO:2446), KFTVDPKD (SEQ ID NO:2447), KFTVDPKTD (SEQ IDNO:2448), KFTVDPKTGD (SEQ ID NO:2449), KHFTVDPKD (SEQ ID NO:2450),KHFTVDPKTD (SEQ ID NO:2451), KHFTVDPKTGD (SEQ ID NO:2452), KDADD (SEQ IDNO:2453), KDADTD (SEQ ID NO:2454), KDADTGD (SEQ ID NO:2455), KIDADD (SEQID NO:2456), KIDADTD (SEQ ID NO:2457), KIDADTGD (SEQ ID NO:2458),KDIDADD (SEQ ID NO:2459), KDIDADTD (SEQ ID NO:2460), KDIDADTGD (SEQ IDNO:2461), KFDIDADD (SEQ ID NO:2462), KFDIDADTD (SEQ ID NO:2463),KFDIDADTGD (SEQ ID NO:2464), KIFDIDADD (SEQ ID NO:2465), KIFDIDADTD (SEQID NO:2466), KIFDIDADTGD (SEQ ID NO:2467), DEEYK (SEQ ID NO:2468),DEEYTK (SEQ ID NO:2469), DEEYTGK (SEQ ID NO:2470), DVEEYK (SEQ IDNO:2471), DVEEYTK (SEQ ID NO:2472), DVEEYTGK (SEQ ID NO:2473), DVVEEYK(SEQ ID NO:2474), DVVEEYTK (SEQ ID NO:2475), DVVEEYTGK (SEQ ID NO:2476),DFVVEEYK (SEQ ID NO:2477), DFVEEYTK (SEQ ID NO:2478), DFVEEYTGK (SEQ IDNO:2479), DFFVVEEYK (SEQ ID NO:2480), DFFVVEEYTK, (SEQ ID NO:2481),DFFVVEEYTGK (SEQ ID NO:2482), DDELK (SEQ ID NO:2483), DDELTK (SEQ IDNO:2484), DDELTGK (SEQ ID NO:2485), DIDELK (SEQ ID NO:2486), DIDELTK(SEQ ID NO:2487), DIDELTGK (SEQ ID NO:2488), DLIDELK (SEQ ID NO:2489),DLIDELTK (SEQ ID NO:2490), DLIDELTGK (SEQ ID NO:2491), DFLIDELK (SEQ IDNO:2492), DFLIDELTK (SEQ ID NO:2493), DFLIDELTGK (SEQ ID NO:2494),DIFLIDELK (SEQ ID NO:2495), DIFLIDELTK (SEQ ID NO:2496), DIFLIDELTGK(SEQ ID NO:2497), DDPKK (SEQ ID NO:2498), DDPKTK (SEQ ID NO:2499),DDPKTGK (SEQ ID NO:2500), DVDPKK (SEQ ID NO:2501), DVDPKYK (SEQ IDNO:2502), DVTPKTGK (SEQ ID NO:2503), DTVDPKK (SEQ ID NO:2504), DTVDPKTK(SEQ ID NO:2505), DTVDPKTGK (SEQ ID NO:2506), DFTVDPKK (SEQ ID NO:2507),DFTVDPKTK (SEQ ID NO:2508), DFTVDPKTGK (SEQ ID NO:2509), DHFTVDPKK (SEQID NO:2510), DHFTVDPKTK (SEQ ID NO:2511), DHFTVDPKTGK (SEQ ID NO:2512),DDADK (SEQ ID NO:2513), DDADTK (SEQ ID NO:2514), DDADTGK (SEQ IDNO:2515), DIDADK (SEQ ID NO:2516), DIDADTK (SEQ ID NO:2517), DIDADTGK(SEQ ID NO:2518), DDIDADK (SEQ ID NO:2519), DDIDADTK (SEQ ID NO:2520),DDIDADTGK (SEQ ID NO:2521), DFDIDADK (SEQ ID NO:2522), DFDIDADTK (SEQ IDNO:2523), DFDIDADTGK (SEQ ID NO:2524), DIFDIDADK (SEQ ID NO:2525),DIFDIDADTK (SEQ ID NO:2526), DIFDIDADTGK (SEQ ID NO:2527), KEEYE (SEQ IDNO:2528), KEEYTE (SEQ ID NO:2529), KEEYTGE (SEQ ID NO:2530), KVEEYE (SEQID NO:2531), KVEEYTE (SEQ ID NO:2532), KVEEYTGE (SEQ ID NO:2533),KVVEEYE (SEQ ID NO:2534), KVVEEYTE (SEQ ID NO:2535), KVVEEYTGE (SEQ IDNO:2536), KFVVEEYE (SEQ ID NO:2537), KFVEEYTE (SEQ ID NO:2538),KFVEEYTGE (SEQ ID NO:2539), KFFVVEEYE (SEQ ID NO:2540), KFFVVEEYTE (SEQID NO:2541), KFFVVEEYTGE (SEQ ID NO:2542), KDELE (SEQ ID NO:2543),KDELTE (SEQ ID NO:2544), KDELTGE (SEQ ID NO:2545), KIDELE (SEQ IDNO:2546), KIDELTE (SEQ ID NO:2547), KIDELTGE (SEQ ID NO:2548), KLIDELE(SEQ ID NO:2549), KLIDELTE (SEQ ID NO:2550), KLIDELTGE (SEQ ID NO:2551),KFLIDELE (SEQ ID NO:2552), KFLIDELTE (SEQ ID NO:2553), KFLIDELTGE (SEQID NO:2554), KIFLIDELE (SEQ ID NO:2555), KIFLIDELTE (SEQ ID NO:2556),KIFLIDELTGE (SEQ ID NO:2557), KDPKE (SEQ ID NO:2558), KDPKTE (SEQ IDNO:2559), KDPKTGE (SEQ ID NO:2560), KVDPKE (SEQ ID NO:2561), KVDPKTE(SEQ ID NO:2562), KDPKTGE (SEQ ID NO:2563), KTVDPKE (SEQ ID NO:2564),KTVDPKTE (SEQ ID NO:2565), KTVDPKTGE (SEQ ID NO:2566), KFTVDPKE (SEQ IDNO:2567), KFTVDPKTE (SEQ ID NO:2568), KFTVDPKTGE (SEQ ID NO:2569),KHFTVDPKE (SEQ ID NO:2570), KHFTVDPKTE (SEQ ID NO:2571), KHFTVDPKTGE(SEQ ID NO:2572), KDADE (SEQ ID NO:2573), KDADTE (SEQ ID NO:2574),KDADTGE (SEQ ID NO:2575), KIDADE (SEQ ID NO:2576), KIDADTE (SEQ IDNO:2577), KIDADTGE (SEQ ID NO:2578), KDIDADE (SEQ ID NO:2579), KDIDADTE(SEQ ID NO:2580), KDIDADTGE (SEQ ID NO:2581), KFDIDADE (SEQ ID NO:2582),KFDIDADTE (SEQ ID NO:2583), KFDIDADTGE (SEQ ID NO:2584), KIFDIDADE (SEQID NO:2585), KIFDIDADTE (SEQ ID NO:2586), KIFDIDADTGE (SEQ ID NO:2587),VEEYT (SEQ ID NO:2588), VEEYTG (SEQ ID NO:2589), VVEEY (SEQ ID NO:2590),VVEEYT (SEQ ID NO:2591), VVEEYTG (SEQ ID NO:2592), FVVEEY (SEQ IDNO:2593), FVEEYT (SEQ ID NO:2594), FVEEYTG (SEQ ID NO:2595), FFVVEEY(SEQ ID NO:2596), FFVVEEYT (SEQ ID NO:2597), FFVVEEYTG (SEQ ID NO:2598),LIDEL (SEQ ID NO:2599), LIDELT (SEQ ID NO:2600), LIDELTG (SEQ IDNO:2601), FLIDEL (SEQ ID NO:2602), FLIDELT (SEQ ID NO:2603), FLIDELTG(SEQ ID NO:2604), IFLIDEL (SEQ ID NO:2605), IFLIDELT (SEQ ID NO:2606),IFLIDELTG (SEQ ID NO:2607), TVDPK (SEQ ID NO:2608), TVDPKT (SEQ IDNO:2609), TVDPKTG (SEQ ID NO:2610), FTVDPK (SEQ ID NO:2611), FTVDPKT(SEQ ID NO:2612), FTVDPKTG (SEQ ID NO:2613), HFTVDPK (SEQ ID NO:2614),HFTVDPKT (SEQ ID NO:2615), HFTVDPKTG (SEQ ID NO:2616), DADTG (SEQ IDNO:2617), IDADT (SEQ ID NO:2618), IDADTG (SEQ ID NO:2619), DIDAD (SEQ IDNO:2620), DIDADT (SEQ ID NO:2621), DIDADTG (SEQ ID NO:2622), FDIDAD (SEQID NO:2623), FDIDADT (SEQ ID NO:2624), FDIDADTG (SEQ ID NO:2625),IFDIDAD (SEQ ID NO:2626), IFDIDADT (SEQ ID NO:2627) and IFDIDADTG (SEQID NO:2628).
 73. A polynucleotide encoding a modulating agent accordingto claim
 69. 74. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to aPB-cadherin CAR sequence selected from the group consisting of FFVVEEYTG(SEQ ID NO:375), IFLIDELTG (SEQ ID NO:389), HFTVDPKTG (SEQ ID NO:403)and IFDIDADTG (SEQ ID NO:417); and (b) modulates a PB-cadherin-mediatedfunction.
 75. A modulating agent according to any one of claims 1-4,wherein the agent comprises one or more LI-cadherin CAR sequencesselected from the group consisting of NNK, NNKT (SEQ ID NO:418), NNKTG(SEQ ID NO:419), INNK (SEQ ID NO:420), INNKT (SEQ ID NO:421), INNKTG(SEQ ID NO:422), QINNK (SEQ ID NO:423), QINNKT (SEQ ID NO:424), QINNKTG(SEQ ID NO:425), FQINNK (SEQ ID NO:426), FQINNKT (SEQ ID NO:427),FQINNKTG (SEQ ID NO:428), YFQINNK (SEQ ID NO:429), YFQINNKT (SEQ IDNO:430) and YFQINNKTG (SEQ ID NO:431);
 76. A modulating agent accordingto claim 75, wherein the agent comprises a linear peptide having thesequence N-Ac-YFQINNKTG-NH₂ (SEQ ID NO:431).
 77. A modulating agentaccording to claim 75, wherein a LI-cadherin CAR sequence is presentwithin a cyclic peptide.
 78. A modulating agent according to claim 77,wherein the cyclic peptide comprises a sequence selected from the groupconsisting of CNNKC (SEQ ID NO:2629), CNNKTC (SEQ ID NO:2630), CNNKTGC(SEQ ID NO:2631), CINNKC (SEQ ID NO:2632), CINNKTC (SEQ ID NO:2633),CINNKTGC (SEQ ID NO:2634), CQINNKC (SEQ ID NO:2635), CQINNKTC (SEQ IDNO:2636), CQINNKTGC (SEQ ID NO:2637), CFQINNKC (SEQ ID NO:2638),CFQINNKTC (SEQ ID NO:2639), CFQINNKTGC (SEQ ID NO:2640), CYFQINNKC (SEQID NO:2641), CYFQINNKTC (SEQ ID NO:2642), CYFQINNKTGC (SEQ ID NO:2643),ENNKK (SEQ ID NO:2644), ENNKTK (SEQ ID NO:2645), ENNKTGK (SEQ IDNO:2646), EINNKK (SEQ ID NO:2647), EINNKTK (SEQ ID NO:2648), EINNKTGK(SEQ ID NO:2649), EQINNKK (SEQ ID NO:2650), EQINNKTK (SEQ ID NO:2651),EQINNKTGK (SEQ ID NO:2652), EFQINNKK (SEQ ID NO:2653), EFQINNKTK (SEQ IDNO:2654), EFQINNKTGK (SEQ ID NO:2655), EYFQINNKK (SEQ ID NO:2656),EYFQINNKTK (SEQ ID NO:2657), EYFQINNKTGK (SEQ ID NO:2658), KNNKD (SEQ IDNO:2659), KNNKTD (SEQ ID NO:2660), KNNKTGD (SEQ ID NO:2661), KINNKD (SEQID NO:2662), KINNKTD (SEQ ID NO:2663), KINNKTGD (SEQ ID NO:2664),KQINNKD (SEQ ID NO:2665), KQINNKTD (SEQ ID NO:2666), KQINNKTGD (SEQ IDNO:2667), KFQINNKD (SEQ ID NO:2668), KFQINNKTD (SEQ ID NO:2669),KFQINNKTGD (SEQ ID NO:2670), KYFQINNKD (SEQ ID NO:2671), KYFQINNKTD (SEQID NO:2672), KYFQINNKTGD (SEQ ID NO:2673), DNNKK (SEQ ID NO:2674),DNNKTK (SEQ ID NO:2675), DNNKTGK (SEQ ID NO:2676), DINNKK (SEQ IDNO:2677), DINNKTK (SEQ ID NO:2678), DINNKTGK (SEQ ID NO:2679), DQINNKK(SEQ ID NO:2680), DQINNKTK (SEQ ID NO:2681), DQINNKTGK (SEQ ID NO:2682),DFQINNKK (SEQ ID NO:2683), DFQINNKTK (SEQ ID NO:2684), DFQINNKTGK (SEQID NO:2685), DYFQINNKK (SEQ ID NO:2686), DYFQINNKTK (SEQ ID NO:2687),DYFQINNKTGK (SEQ ID NO:2688), KNNKE (SEQ ID NO:2689), KNNKTE (SEQ IDNO:2690), KNNKTGE (SEQ ID NO:2691), KINNKE (SEQ ID NO:2692), KINNKTE(SEQ ID NO:2693), KINNKTGE (SEQ ID NO:2694), KQINNKE (SEQ ID NO:2695),KQINNKTE (SEQ ID NO:2696), KQINNKTGE (SEQ ID NO:2697), KFQINNKE (SEQ IDNO:2698), KFQINNKTE (SEQ ID NO:2699), KFQINNKTGE (SEQ ID NO:2700),KYFQINNKE (SEQ ID NO:2701), KYFQINNKTE (SEQ ID NO:2702), KYFQINNKTGE(SEQ ID NO:2703), NNKTG (SEQ ID NO:2704), INNKT (SEQ ID NO:2705), INNKTG(SEQ ID NO:2706), QINNK (SEQ ID NO:2707), QINNKT (SEQ ID NO:2708),QINNKTG (SEQ ID NO:2709), FQINNK (SEQ ID NO:2710), FQINNKT (SEQ IDNO:2711), FQINNKTG (SEQ ID NO:2712), YFQINNK (SEQ ID NO:2713), YFQINNKT(SEQ ID NO:2714) and YFQINNKTG (SEQ ID NO:2715).
 79. A polynucleotideencoding a modulating agent according to claim
 75. 80. A modulatingagent comprising an antibody or antigen-binding fragment thereof that:(a) specifically binds to the LI-cadherin CAR sequence YFQINNKTG (SEQ IDNO:431); and (b) modulates a LI-cadherin-mediated function.
 81. Amodulating agent according to any one of claims 1-4, wherein the agentcomprises one or more protocadherin CAR sequences selected from thegroup consisting DLV, DLVT (SEQ ID NO:432), DLVTG (SEQ ID NO:433), LDLV(SEQ ID NO:434), LDLVT (SEQ ID NO:435), LDLVTG (SEQ ID NO:436), ALDLV(SEQ ID NO:437), ALDLVT (SEQ ID NO:438), ALDLVTG (SEQ ID NO:439), FALDLV(SEQ ID NO:440), FALDLVT (SEQ ID NO:441), FALDLVTG (SEQ ID NO:442),LFALDLV (SEQ ID NO:443), LFALDLVT (SEQ ID NO:444), LFALDLVTG (SEQ IDNO:445), NRD, NRDN (SEQ ID NO:446), NRDNG (SEQ ID NO:447), INRD (SEQ IDNO:448), INRDN (SEQ ID NO:449), INRDNG (SEQ ID NO:450), TINRD (SEQ IDNO:451), TINRDN (SEQ ID NO:452), TINRDNG (SEQ ID NO:453), FTINRD (SEQ IDNO:454), FTINRDN (SEQ ID NO:455), FTINRDNG (SEQ ID NO:456), YFTINRD (SEQID NO:457), YFTINRDN (SEQ ID NO:458), YFTINRDNG (SEQ ID NO:459), DPK,DPKT (SEQ ID NO:460), DPKTG (SEQ ID NO:461), IDPK (SEQ ID NO:462), IDPKT(SEQ ID NO:463), IDPKTG (SEQ ID NO:464), SIDPK (SEQ ID NO:465), SIDPKT(SEQ ID NO:466), SIDPKTG (SEQ ID NO:467), FSIDPK (SEQ ID NO:468),FSIDPKT (SEQ ID NO:469), FSIDPKTG (SEQ ID NO:470), LFSIDPK (SEQ IDNO:471), LFSIDPKT (SEQ ID NO:472), LFSIDPKTG (SEQ ID NO:473), DPS, DPSS(SEQ ID NO:474), DPSSG (SEQ ID NO:475), IDPS (SEQ ID NO:476), IDPSS (SEQID NO:477), IDPSSG (SEQ ID NO:478), EIDPS (SEQ ID NO:479), EIDPSS (SEQID NO:480), EIDPSSG (SEQ ID NO:481), FEIDPS (SEQ ID NO:482), FEIDPSS(SEQ ID NO:483), FEIDPS (SEQ ID NO:484), FEIDPSS (SEQ ID NO:485),FEIDPSSG (SEQ ID NO:486), LFEIDPS (SEQ ID NO:487), LFEIDPSS (SEQ IDNO:488) and LFEIDPSSG (SEQ ID NO:489).
 82. A modulating agent accordingto claim 81, wherein the agent comprises a linear peptide having thesequence N-Ac-LFALDLVTG-NH₂ (SEQ ID NO:445), N-Ac-YFTINRDNG-NH₂ (SEQ IDNO:459), N-Ac-LFSIDPKTG-NH₂ (SEQ ID NO:473) or N-Ac-LFEIDPSSG-NH₂ (SEQID NO:489).
 83. A modulating agent according to claim 81, wherein aprotocadherin CAR sequence is present within a cyclic peptide.
 84. Amodulating agent according to claim 83, wherein the cyclic peptidecomprises a sequence selected from the group consisting of CDLVC (SEQ IDNO:2716), CDLVTC (SEQ ID NO:2717), CDLVTGC (SEQ ID NO:2718), CLDLVC (SEQID NO:2719), CLDLVTC (SEQ ID NO:2720), CLDLVTGC (SEQ ID NO:2721),CALDLVC (SEQ ID NO:2722), CALDLVTC (SEQ ID NO:2723), CALDLVTGC (SEQ IDNO:2724), CFALDLVC (SEQ ID NO:2725), CFALDLVTC (SEQ ID NO:2726),CFALDLVTGC (SEQ ID NO:2727), CLFALDLVC (SEQ ID NO:2728), CLFALDLVTC (SEQID NO:2729), CLFALDLVTGC (SEQ ID NO:2730), CNRDC (SEQ ID NO:2731),CNRDNC (SEQ ID NO:2732), CNRDNGC (SEQ ID NO:2733), CINRDC (SEQ IDNO:2734), CINRDNC (SEQ ID NO:2735), CINRDNGC (SEQ ID NO:2736), CTINRDC(SEQ ID NO:2737), CTINRDNC (SEQ ID NO:2738), CTINRDNGC (SEQ ID NO:2739),CFTINRDC (SEQ ID NO:2740), CFTINRDNC (SEQ ID NO:2741), CFTINRDNGC (SEQID NO:2742), CYFTINRDC (SEQ ID NO:2743), CYFTINRDNC (SEQ ID NO:2744),CYFTINRDNGC (SEQ ID NO:2745), CDPSC (SEQ ID NO:2746), CDPSSC (SEQ IDNO:2747), CDPSSGC (SEQ ID NO:2748), CIDPSC (SEQ ID NO:2749), CIDPSSC(SEQ ID NO:2750), CIDPSSGC (SEQ ID NO:2751), CEIDPSC (SEQ ID NO:2752),CEIDPSSC (SEQ ID NO:2753), CEIDPSSGC (SEQ ID NO:2754), CFEIDPSC (SEQ IDNO:2755), CFEIDPSSC (SEQ ID NO:2756), CEIDPSSGC (SEQ ID NO:2757),CFEIDPSC (SEQ ID NO:2758), CFEIDPSSC (SEQ ID NO:2759), CFEIDPSSGC (SEQID NO:2760), CLFEIDPSC (SEQ ID NO:2761), CLFEIDPSSC (SEQ ID NO:2762),CLFEIDPSSGC (SEQ ID NO:2763), EDLVK (SEQ ID NO:2764), EDLVTK (SEQ IDNO:2765), EDLVTGK (SEQ ID NO:2766), ELDLVK (SEQ ID NO:2767), ELDLVTK(SEQ ID NO:2768), ELDLVTGK (SEQ ID NO:2769), EALDLVK (SEQ ID NO:2770),EALDLVTK (SEQ ID NO:2771), EALDLVTGK (SEQ ID NO:2772), EFALDLVK-(SEQ IDNO:2773), EFALDLVTK (SEQ ID NO:2774), EFALDLVTGK (SEQ ID NO:2775),ELFALDLVK (SEQ ID NO:2776), ELFALDLVTK (SEQ ID NO:2777), ELFALDLVTGK(SEQ ID NO:2778), ENRDK (SEQ ID NO:2779), ENRDNK (SEQ ID NO:2780),ENRDNGK (SEQ ID NO:2781), EINRDK (SEQ ID NO:2782), EINRDNK (SEQ IDNO:2783), EINRDNGK (SEQ ID NO:2784), ETINRDK (SEQ ID NO:2785), ETINRDNK(SEQ ID NO:2786), ETINRDNGK (SEQ ID NO:2787), EFTINRDK (SEQ ID NO:2788),EFTINRDNK (SEQ ID NO:2789), EFTINRDNGK (SEQ ID NO:2790), EYFTINRDK (SEQID NO:2791), EYFTINRDNK (SEQ ID NO:2792), EYFTINRDNGK (SEQ ID NO:2793),EDPKK (SEQ ID NO:2794), EDPKTK (SEQ ID NO:2795), EDPKTGK (SEQ IDNO:2796), EIDPKK (SEQ ID NO:2797), EIDPKTK (SEQ ID NO:2798), EIDPKTGK(SEQ ID NO:2799), ESIDPKK (SEQ ID NO:2800), ESIDPKTK (SEQ ID NO:2801),ESIDPKTGK (SEQ ID NO:2802), EFSIDPKK (SEQ ID NO:2803), EFSIDPKTK (SEQ IDNO:2804), EFSIDPKTGK (SEQ ID NO:2805), ELFSIDPKK (SEQ ID NO:2806),ELFSIDPKTK (SEQ ID NO:2807), ELFSIDPKTGK (SEQ ID NO:2808), EDPSK (SEQ IDNO:2809), EDPSSK (SEQ ID.NO:2810), EDPSSGK (SEQ ID NO:2811), EIDPSK (SEQID NO:2812), EIDPSSK (SEQ ID NO:2813), EIDPSSGK (SEQ ID NO:2814),EEIDPSK (SEQ ID NO:2815), EEIDPSSK (SEQ ID NO:2816), EEIDPSSGK (SEQ IDNO:2817), EFEIDPSK (SEQ ID NO:2818), EFEIDPSSK (SEQ ID NO:2819),EEIDPSSGK (SEQ ID NO:2820), EFEIDPSK (SEQ ID NO:2821), EFEIDPSSK (SEQ IDNO:2822), EFEIDPSSGK (SEQ ID NO:2823), ELFEIDPSK (SEQ ID NO:2824),ELFEIDPSSK (SEQ ID NO:2825), ELFEIDPSSGK (SEQ ID NO:2826), KDLVD (SEQ IDNO:2827), KDLVTD (SEQ ID NO:2828), KDLVTGD (SEQ ID NO:2829), KLDLVD (SEQID NO:2830), KLDLVTD (SEQ ID NO:2831), KLDLVTGD (SEQ ID NO:2832),KALDLVD (SEQ ID NO:2833), KALDLVTD (SEQ ID NO:2834), KALDLVTGD (SEQ IDNO:2835), KFALDLVD (SEQ ID NO:2836), KFALDLVTD (SEQ ID NO:2837),KFALDLVTGD (SEQ ID NO:2838), KLFALDLVD (SEQ ID NO:2839), KLFALDLVTD (SEQID NO:2840), KLFALDLVTGD (SEQ ID NO:2841), KNRDD (SEQ ID NO:2842),KNRDND (SEQ ID NO:2843), KNRDNGD (SEQ ID NO:2844), KINRDD (SEQ IDNO:2845), KINRDND (SEQ ID NO:2846), KINRDNGD (SEQ ID NO:2847), KTINRDD(SEQ ID NO:2848), KTINRDND (SEQ ID NO:2849), KTINRDNGD (SEQ ID NO:2850),KFTINRDD (SEQ ID NO:2851), KFTINRDND (SEQ ID NO:2852), KFTINRDNGD (SEQID NO:2853), KYFTINRDD (SEQ ID NO:2854), KYFTINRDND (SEQ ID NO:2855),KYFTINRDNGD (SEQ ID NO:2856), KDPKD (SEQ ID NO:2857), KDPKTD (SEQ IDNO:2858), KDPKTGD (SEQ ID NO:2859), KIDPKD (SEQ ID NO:2860), KIDPKTD(SEQ ID NO:2861), KIDPKTGD (SEQ ID NO:2862), KSIDPKD (SEQ ID NO:2863),KSIDPKTD (SEQ ID NO:2864), KSIDPKTGD (SEQ ID NO:2865), KFSIDPKD (SEQ IDNO:2866), KFSIDPKTD (SEQ ID NO:2867), KFSIDPKTGD (SEQ ID NO:2868),KLFSIDPKD (SEQ ID NO:2869), KLFSIDPKTD (SEQ ID NO:2870), KLFSIDPKTGD(SEQ ID NO:2871), KDPSD (SEQ ID NO:2872), KDPSSD (SEQ ID NO:2873),KDPSSGD (SEQ ID NO:2874), KIDPSD (SEQ ID NO:2875), KIDPSSD (SEQ IDNO:2876), KIDPSSGD (SEQ ID NO:2877), KEIDPSD (SEQ ID NO:2878), KEIDPSSD(SEQ ID NO:2879), KEIDPSSGD (SEQ ID NO:2880), KFEIDPSD (SEQ ID NO:2881),KFEIDPSSD (SEQ ID NO:2882), KFEIDPSSGD (SEQ ID NO:2886), KLFEIDPSD (SEQID NO:2887), KLFEIDPSSD (SEQ ID NO:2888), KLFEIDPSSGD (SEQ ID NO:2889),KDLVE (SEQ ID NO:2890), KDLVTE (SEQ ID NO:2891), KDLVTGE (SEQ IDNO:2892), KLDLVE (SEQ ID NO:2893), KLDLVTE (SEQ ID NO:2894), KLDLVTGE(SEQ ID NO:2895), KALDLVE (SEQ ID NO:2896), KALDLVTE (SEQ ID NO:2897),KALDLVTGE (SEQ ID NO:2898), KFALDLVE (SEQ ID NO:2899), KFALDLVTE (SEQ IDNO:2900), KFALDLVTGE (SEQ ID NO:2901), KLFALDLVE (SEQ ID NO:2902),KLFALDLVTE (SEQ ID NO:2903), KLFALDLVTGE (SEQ ID NO:2904), KNRDE (SEQ IDNO:2905), KNRDNE (SEQ ID NO:2906), KNRDNGE (SEQ ID NO:2907), KINRDE (SEQID NO:2908), KINRDNE (SEQ ID NO:2909), KINRDNGE (SEQ ID NO:2910),KTINRDE (SEQ ID NO:2911), KTINRDNE (SEQ ID NO:2912), KTINRDNGE (SEQ IDNO:2913), KFTINRDE (SEQ ID NO:2914), KFTINRDNE (SEQ ID NO:2915),KFTINRDNGE (SEQ ID NO:2916), KYFTINRDE (SEQ ID NO:2917), KYFTINRDNE (SEQID NO:2918), KYFTINRDNGE (SEQ ID NO:2919), KDPKE (SEQ ID NO:2920),KDPKTE (SEQ ID NO:2921), KDPKTGE (SEQ ID NO:2922), KIDPKE (SEQ IDNO:2923), KIDPKTE (SEQ ID NO:2924), KIDPKTGE (SEQ ID NO:2925), KSIDPKE(SEQ ID NO:2926), KSIDPKTE (SEQ ID NO:2927), KSIDPKTGE (SEQ ID NO:2928),KFSIDPKE (SEQ ID NO:2929), KFSIDPKTE (SEQ ID NO:2930), KFSIDPKTGE (SEQID NO:2931), KLFSIDPKE (SEQ ID NO:2932), KLFSIDPKTE (SEQ ID NO:2933),KLFSIDPKTGE (SEQ ID NO:2934), KDPSE (SEQ ID NO:2935), KDPSSE (SEQ IDNO:2936), KDPSSGE (SEQ ID NO:2937), KIDPSE (SEQ ID NO:2938), KIDPSSE(SEQ ID NO:2939), KIDPSSGE (SEQ ID NO:2940), KEIDPSE (SEQ ID NO:2941),KEIDPSSE (SEQ ID NO:2942), KEIDPSSGE (SEQ ID NO:2943), KFEIDPSE (SEQ IDNO:2944), KFEIDPSSE (SEQ ID NO:2945), KFEIDPSSGE (SEQ ID NO:2949),KLFEIDPSE (SEQ ID NO:2950), KLFEIDPSSE (SEQ ID NO:2951), KLFEIDPSSGE(SEQ ID NO:2952), DDLVK (SEQ ID NO:2953), DDLVTK (SEQ ID NO:2954),DDLVTGK (SEQ ID NO:2955), DLDLVK (SEQ ID NO:2956), DLDLVTK (SEQ IDNO:2957), DLDLVTGK (SEQ ID NO:2958), DALDLVK (SEQ ID NO:2959), DALDLVTK(SEQ ID NO:2960), DALDLVTGK (SEQ ID NO:2961), DFALDLVK (SEQ ID NO:2962),DFALDLVTK (SEQ ID NO:2963), DFALDLVTGK (SEQ ID NO:2964), DLFALDLVK (SEQID NO:2965), DLFALDLVTK (SEQ ID NO:2966), DLFALDLVTGK (SEQ ID NO:2967),DNRDK (SEQ ID NO:2968), DNRDNK (SEQ ID NO:2969), DNRDNGK (SEQ IDNO:2970), DINRDK (SEQ ID NO:2971), DINRDNK (SEQ ID NO:2972), DINRDNGK(SEQ ID NO:2973), DTINRDK (SEQ ID NO:2974), DTINRDNK (SEQ ID NO:2975),DTINRDNGK (SEQ ID NO:2976), DFTINRDK (SEQ ID NO:2977), DFTINRDNK (SEQ IDNO:2978), DFTINRDNGK (SEQ ID NO:2979), DYFTINRDK (SEQ ID NO:2980),DYFTINRDNK (SEQ ID NO:2981), DYFTINRDNGK (SEQ ID NO:2982), DDPKK (SEQ IDNO:2983), DDPKTK (SEQ ID NO:2984), DDPKTGK (SEQ ID NO:2985), DIDPKK (SEQID NO:2986), DIDPKTK (SEQ ID NO:2987), DIDPKTGD (SEQ ID NO:2988),DSIDPKK (SEQ ID NO:2989), DSIDPKTK (SEQ ID NO:2990), DSIDPKTGK (SEQ IDNO:2991), DFSIDPKK (SEQ ID NO:2992), DFSIDPKTK (SEQ ID NO:2993),DFSIDPKTGK (SEQ ID NO:2994), DLFSIDPKK (SEQ ID NO:2995), DLFSIDPKTK (SEQID NO:2996), DLFSIDPKTGK (SEQ ID NO:2997), DDPSK (SEQ ID NO:2998),DDPSSK (SEQ ID NO:2999), DDPSSGK (SEQ ID NO:3000), DIDPSK (SEQ IDNO:3001), DIDPSSK (SEQ ID NO:3002), DIDPSSGK (SEQ ID NO:3003), DEIDPSK(SEQ ID NO:3004), DEIDPSSK (SEQ ID NO:3005), DEIDPSSGK (SEQ ID NO:3006),DFEIDPSK (SEQ ID NO:3007), DFEIDPSSK (SEQ ID NO:3008), DFEIDPSSGK (SEQID NO:3012), DLFEIDPSK (SEQ ID NO:3013), DLFEIDPSSK (SEQ ID NO:3014),DLFEIDPSSGK (SEQ ID NO:3015), DLVTG (SEQ ID NO:3016), LDLVT (SEQ IDNO:3017), LDLVTG (SEQ ID NO:3018), ALDLV (SEQ ID NO:3019), ALDLVT (SEQID NO:3020), ALDLVTG (SEQ ID NO:3021), FALDLV (SEQ ID NO:3022), FALDLVTC(SEQ ID NO:3023), FALDLVTG (SEQ ID NO:3024), LFALDLV (SEQ ID NO:3025),LFALDLVT (SEQ ID NO:3026), LFALDLVTG (SEQ ID NO:3027), NRDNG (SEQ IDNO:3028), INRDN (SEQ ID NO:3029), INRDNG (SEQ ID NO:3030), TINRD (SEQ IDNO:3031), TINRDN (SEQ ID NO:3032), TINRDNG (SEQ ID NO:3033), FTINRD (SEQID NO:3034), FTINRDN (SEQ ID NO:3035), FTINRDNG (SEQ ID NO:3036),YFTINRD (SEQ ID NO:3037), YFTINRDN (SEQ ID NO:3038), YFTINRDNG (SEQ IDNO:3039), DPKTG (SEQ ID NO:3040), IDPKT (SEQ ID NO:3041), IDPKTG (SEQ IDNO:3042), SIDPK (SEQ ID NO:3043), SIDPKT (SEQ ID NO:3044), SIDPKTG (SEQID NO:3045), FSIDPK (SEQ ID NO:3046), FSIDPKT (SEQ ID NO:3047), FSIDPKTG(SEQ ID NO:3048), LFSIDPK (SEQ ID NO:3049), LFSIDPKT (SEQ ID NO:3050),LFSIDPKTG (SEQ ID NO:3051), DPSSG (SEQ ID NO:3052), IDPSS (SEQ IDNO:3053), IDPSSG (SEQ ID NO:3054), EIDPSS (SEQ ID NO:3056), EIDPSSG (SEQID NO:3057), FEIDPS (SEQ ID NO:3058), FEIDPSS (SEQ ID NO:3059), EIDPSSG(SEQ ID NO:3060), FEIDPS (SEQ ID NO:3061), FEIDPSSG (SEQ ID NO:3062),LFEIDPS (SEQ ID NO:3063), LFEIDPSS (SEQ ID NO:3064) and LFEIDPSSG (SEQID NO:3065).
 85. A polynucleotide encoding a modulating agent accordingto claim
 81. 86. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to aprotocadherin CAR sequence selected from the group consisting ofLFALDLVTG (SEQ ID NO:445), YFTINRDNG (SEQ ID NO:459), LFSIDPKTG (SEQ IDNO:473) and LFEIDPSSG (SEQ ID NO:489); and (b) modulates aprotocadherin-mediated function.
 87. A modulating agent according to anyone of claims 1-4, wherein the agent comprises one or more desmogleinCAR sequences selected from the group consisting NQK, NQKT (SEQ IDNO:490), NQKTG (SEQ ID NO:491), INQK (SEQ ID NO:492), INQKT (SEQ IDNO:493), INQKTG (SEQ ID NO:494), VINQK (SEQ ID NO:495), VINQKT (SEQ IDNO:496), VINQKTG (SEQ ID NO:497), FVINQK (SEQ ID NO:498), FVINQKT (SEQID NO:499), FVINQKTG (SEQ ID NO:500), IFVINQK (SEQ ID NO:501), IFVINQKT(SEQ ID NO:502), IFVINQKTG (SEQ ID NO:503), NRN, NRNT (SEQ ID NO:504),NRNTG (SEQ ID NO:505), INRN (SEQ ID NO:506), INRNT (SEQ ID NO:507),INRNTG (SEQ ID NO:508), IINRN (SEQ ID NO:509), IINRNT (SEQ ID NO:510),IINRNTG (SEQ ID NO:511), FIINRN (SEQ ID NO:512), FIINRNT (SEQ IDNO:513), FIINRNTG (SEQ ID NO:514), MFIINRN (SEQ ID NO:515), MFIINRNT(SEQ ID NO:516), MFIINRNTG (SEQ ID NO:517), NKD, NKDT (SEQ ID NO:518),NKDTG (SEQ ID NO:519), LNKD (SEQ ID NO:520), LNKDT (SEQ ID NO:521),LNKDTG (SEQ ID NO:522), YLNKD (SEQ ID NO:523), YLNKDT (SEQ ID NO:524),YLNKDTG (SEQ ID NO:525), FYLNKD (SEQ ID NO:526), FYLNKDT (SEQ IDNO:527), FYLNKDTG (SEQ ID NO:528), VFYLNKD (SEQ ID NO:529), VFYLNKDT(SEQ ID NO:530) and VFYLNKDTG (SEQ ID NO:531).
 88. A modulating agentaccording to claim 87, wherein the agent comprises a linear peptidehaving the sequence N-Ac-IFVINQKTG-NH₂ (SEQ ID NO:503),N-Ac-MFIINRNTG-NH₂ (SEQ ID NO:517) or N-Ac-VFYLNKDTG-NH₂ (SEQ IDNO:531).
 89. A modulating agent according to claim 87, wherein adesmoglein CAR sequence is present within a cyclic peptide.
 90. Amodulating agent according to claim 89, wherein the cyclic peptidecomprises a sequence selected from the group consisting of CNQKC (SEQ IDNO:3066), CNQKTC (SEQ ID NO:3067), CNQKTGC (SEQ ID NO:3068), CINQKC (SEQID NO:3069), CINQKTC (SEQ ID NO:3070), CINQKTGC (SEQ ID NO:3071),CVINQKC (SEQ ID NO:3072), CVINQKTC (SEQ ID NO:3073), CVINQKTGC (SEQ IDNO:3074), CFVINQKC (SEQ ID NO:3075), CFVINQKTC (SEQ ID NO:3076),CFVINQKTGC (SEQ ID NO:3077), CIFVINQKC (SEQ ID NO:3078), CIFVINQKTC (SEQID NO:3079), CIFVINQKTGC (SEQ ID NO:3080), CNRNC (SEQ ID NO:3081),CNRNTC (SEQ ID NO:3082), CNRNTGC (SEQ ID NO:3083), CINRNC (SEQ IDNO:3084), CINRNTC (SEQ ID NO:3085), CINRNTGC (SEQ ID NO:3086), CIINRNC(SEQ ID NO:3087), CIINRNTC (SEQ ID NO:3088), CIINRNTGC (SEQ ID NO:3089),CFIINRNC (SEQ ID NO:3090), CFIINRNTC (SEQ ID NO:3091), CFIINRNTGC (SEQID NO:3092), CMFIINRNC (SEQ ID NO:3093), CMFIINRNTC (SEQ ID NO:3094),CMFIINRNTGC (SEQ ID NO:3095), CNKDC (SEQ ID NO:3096), CNKDTC (SEQ IDNO:3097), CNKDTGC (SEQ ID NO:3098), CLNKDC (SEQ ID NO:3099), CLNKDTC(SEQ ID NO:3100), CLNKDTGC (SEQ ID NO:3101), CYLNKDC (SEQ ID NO:3102),CYLNKDTC (SEQ ID NO:3103), CYLNKDTGC (SEQ ID NO:3104), CFYLNKDC (SEQ IDNO:3105), CFYLNKDTC (SEQ ID NO:3106), CFYLNKDTGC (SEQ ID NO:3107),CVFYLNKDC (SEQ ID NO:3108), CVFYLNKDTC (SEQ ID NO:3109), CVFYLNKDTGC(SEQ ID NO:3110), ENQKK (SEQ ID NO:3111), ENQKTK (SEQ ID NO:3112),ENQKTGK (SEQ ID NO:3113), EINQKK (SEQ ID NO:3114), EINQKTK (SEQ IDNO:3115), EINQKTGK (SEQ ID NO:3116), EVINQKK (SEQ ID NO:3117), EVINQKTK(SEQ ID NO:3118), EVINQKTGK (SEQ ID NO:3119), EFVINQKK (SEQ ID NO:3120),EFVINQKTK (SEQ ID NO:3121), EFVINQKTGK (SEQ ID NO:3122), EIFVINQKK (SEQID NO:3123), EIFVINQKTK (SEQ ID NO:3124), EIFVINQKTGK (SEQ ID NO:3125),ENRNK (SEQ ID NO:3126), ENRNTK (SEQ ID NO:3127), ENRNTGK (SEQ IDNO:3128), EINRNK (SEQ ID NO:3129), EINRNTK (SEQ ID NO:3130), EINRNTGK(SEQ ID NO:3131), EIINRNK (SEQ ID NO:3132), EIINRNTK (SEQ ID NO:3133),EIINRNTGK (SEQ ID NO:3134), EFIINRNK (SEQ ID NO:3135), EFIINRNTK (SEQ IDNO:3136), EFIINRNTGK (SEQ ID NO:3137), EMFIINRNK (SEQ ID NO:3138),EMFIINRNTK (SEQ ID NO:3139), EMFIINRNTGK (SEQ ID NO:3140), ENKDK (SEQ IDNO:3141), ENKDTK (SEQ ID NO:3142), ENKDTGK (SEQ ID NO:3143), ELNKDK (SEQID NO:3144), ELNKDTK (SEQ ID NO:3145), ELNKDTGK (SEQ ID NO:3146),EYLNKDK (SEQ ID NO:3147), EYLNKDTK (SEQ ID NO:3148), EYLNKDTGK (SEQ IDNO:3149), EFYLNKDK (SEQ ID NO:3150), EFYLNKDTK (SEQ ID NO:3151),EFYLNKDTGK (SEQ ID NO:3152), EVFYLNKDK (SEQ ID NO:3153), EVFYLNKDTK (SEQID NO:3154), EVFYLNKDTGK (SEQ ID NO:3155), KNQKD (SEQ ID NO:3156),KNQKTD (SEQ ID NO:3157), KNQKTGD (SEQ ID NO:3158), KINQKD (SEQ IDNO:3159), KINQKTD (SEQ ID NO:3160), KINQKTGD (SEQ ID NO:3161), KVINQKD(SEQ ID NO:3162), KVINQKTD (SEQ ID NO:3163), KVINQKTGD (SEQ ID NO:3164),KFVINQKD (SEQ ID NO:3165), KFVINQKTD (SEQ ID NO:3166), KFVINQKTGD (SEQID NO:3167), KIFVINQKD (SEQ ID NO:3168), KIFVINQKTD (SEQ ID NO:3169),KIFVINQKTGD (SEQ ID NO:3170), KNRND (SEQ ID NO:3171), KNRNTD (SEQ IDNO:3172), KNRNTGD (SEQ ID NO:3173), KINRND (SEQ ID NO:3174), KINRNTD(SEQ ID NO:3175), KINRNTGD (SEQ ID NO:3176), KIINRND (SEQ ID NO:3177),KIINRNTD (SEQ ID NO:3178), KIINRNTGD (SEQ ID NO:3179), KFIINRND (SEQ IDNO:3180), KFIINRNTD (SEQ ID NO:3181), KFIINRNTGD (SEQ ID NO:3182),KMFIINRND (SEQ ID NO:3183), KMFIINRNTD (SEQ ID NO:3184), KMFIINRNTGD(SEQ ID NO:3185), KNKDD (SEQ ID NO:3186), KNKDTD (SEQ ID NO:3187),KNKDTGD (SEQ ID NO:3188), KLNKDD (SEQ ID NO:3189), KLNKDTD (SEQ IDNO:3190) KLNKDTGD (SEQ ID NO:3191), KYLNKDD (SEQ ID NO:3192), KYLNKDTD(SEQ ID NO:3193), KYLNKDTGD (SEQ ID NO:3194), KFYLNKDD (SEQ ID NO:3195),KFYLNKDTD (SEQ ID NO:3196), KFYLNKDTGD (SEQ ID NO:3197), KVFYLNKDD (SEQID NO:3198), KVFYLNKDTD (SEQ ID NO:3199), KVFYLNKDTGD (SEQ ID NO:3200),DNQKK (SEQ ID NO:3201), DNQKTK (SEQ ID NO:3202), DNQKTGK (SEQ IDNO:3203), DINQKK (SEQ ID NO:3204), DINQKTK (SEQ ID NO:3205), DINQKTGK(SEQ ID NO:3206), DVINQKK (SEQ ID NO:3207), DVINQKTK (SEQ ID NO:3208),DVINQKTGK (SEQ ID NO:3209), DFVINQKK (SEQ ID NO:3210), DFVINQKTK (SEQ IDNO:3211), DFVINQKTGK (SEQ ID NO:3212), DIFVINQKK (SEQ ID NO:3213),DIFVINQKTK (SEQ ID NO:3214), DIFVINQKTGK (SEQ ID NO:3215), DNRNK (SEQ IDNO:3216), DNRNTK (SEQ ID NO:3217), DNRNTGK (SEQ ID NO:3218), DINRNK (SEQID NO:3219), DINRNTK (SEQ ID NO:3220), DINRNTGK (SEQ ID NO:3221),DIINRNK (SEQ ID NO:3222), DIINRNTK (SEQ ID NO:3223), DIINRNTGK (SEQ IDNO:3224), DFIINRNK (SEQ ID NO:3225), DFIINRNTK (SEQ ID NO:3226),DFIINRNTGK (SEQ ID NO:3227), DMFIINRNK (SEQ ID NO:3228), DMFIINRNTK (SEQID NO:3229), DMFIINRNTGK (SEQ ID NO:3230), DNKDK (SEQ ID NO:3231),DNKDTK (SEQ ID NO:3232), DNKDTGK (SEQ ID NO:3233), DLNKDK (SEQ IDNO:3234), DLNKDTK (SEQ ID NO:3235), DLNKDTGK (SEQ ID NO:3236), DYLNKDK(SEQ ID NO:3237), DYLNKDTK (SEQ ID NO:3238), DYLNKDTGK (SEQ ID NO:3239),DFYLNKDK (SEQ ID NO:3240), DFYLNKDTK (SEQ ID NO:3241), DFYLNKDTGK (SEQID NO:3242), DVFYLNKDK (SEQ ID NO:3243), DVFYLNKDTK (SEQ ID NO:3244),DVFYLNKDTGK (SEQ ID NO:3245), KKNQKE (SEQ ID NO:3246), KNQKTE (SEQ IDNO:3247), KNQKTGE (SEQ ID NO:3248), KINQKE (SEQ ID NO:3249), KINQKTE(SEQ ID NO:3250), KINQKTGE (SEQ ID NO:3251), KVINQKE (SEQ ID NO:3252),KVINQKTE (SEQ ID NO:3253), KVINQKTGE (SEQ ID NO:3254), KFVINQKE (SEQ IDNO:3255), KFVINQKTE (SEQ ID NO:3256), KFVINQKTGE (SEQ ID NO:3257),KIFVINQKE (SEQ ID NO:3258), KIFVINQKTE (SEQ ID NO:3259), KIFVINQKTGE(SEQ ID NO:3260), KNRNE (SEQ ID NO:3261), KNRNTE (SEQ ID NO:3262),KNRNTGE (SEQ ID NO:3263), KINRNE (SEQ ID NO:3264), KINRNTE (SEQ IDNO:3265), KINRNTGE (SEQ ID NO:3266), KIINRNE (SEQ ID NO:3267), KIINRNTE(SEQ ID NO:3268), KIINRNTGE (SEQ ID NO:3269), KFIINRNE (SEQ ID NO:3270),KFIINRNTE (SEQ ID NO:3271), KFIINRNTGE (SEQ ID NO:3272), KMFIINRNE (SEQID NO:3273), KMFIINRNTE (SEQ ID NO:3274), KMFIINRNTGE (SEQ ID NO:3275),KNKDE (SEQ ID NO:3276), KNKDTE (SEQ ID NO:3277), KNKDTGE (SEQ IDNO:3278), KLNKDE (SEQ ID NO:3279), KLNKDTE (SEQ ID NO:3280), KLNKDTGE(SEQ ID NO:3281), KYLNKDE (SEQ ID NO:3282), KYLNKDTE (SEQ ID NO:3283),KYLNKDTGE (SEQ ID NO:3284), KFYLNKDE (SEQ ID NO:3285), KFYLNKDTE (SEQ IDNO:3286), KFYLNKDTGE (SEQ ID NO:3287), KVFYLNKDE (SEQ ID NO:3288),KVFYLNKDTE (SEQ ID NO:3289), KVFYLNKDTGE (SEQ ID NO:3290), NQKTG (SEQ IDNO:3291), INQKT (SEQ ID NO:3292), INQKTG (SEQ ID NO:3293), VINQK (SEQ IDNO:3294), VINQKT (SEQ ID NO:3295), VINQKTG (SEQ ID NO:3296), FVINQK (SEQID NO:3297), FVINQKT (SEQ ID NO:3298), FVINQKTG (SEQ ID NO:3299),IFVINQK (SEQ ID NO:3300), IFVINQKT (SEQ ID NO:3301), IFVINQKTG (SEQ IDNO:3302), NRNTG (SEQ ID NO:3303), INRNT (SEQ ID NO:3304), INRNTG (SEQ IDNO:3305), IINRN (SEQ ID NO:3306), IINRNT (SEQ ID NO:3307), IINRNTG (SEQID NO:3308), FIINRN (SEQ ID NO:3309), FIINRNT (SEQ ID NO:3310), FIINRNTG(SEQ ID NO:3311), MFIINRN (SEQ ID NO:3312), MFIINRNT (SEQ ID NO:3313),MFIINRNTG (SEQ ID NO:3314), NKDTG (SEQ ID NO:3315), LNKDT (SEQ IDNO:3316), LNKDTG (SEQ ID NO:3317), YLNKD (SEQ ID NO:3318), YLNKDT (SEQID NO:3319), YLNKDTG (SEQ ID NO:3320), FYLNKD (SEQ ID NO:3321), FYLNKDT(SEQ ID NO:3322), FYLNKDTG (SE Q ID NO:3323), VFYLNKD (SEQ ID NO:3324),VFYLNKDT (SEQ ID NO:3325) and VFYLNKDTG (SEQ ID NO:3326).
 91. Apolynucleotide encoding a modulating agent according to claim
 87. 92. Amodulating agent comprising an antibody or antigen-binding fragmentthereof that: (a) specifically binds to a desmoglein CAR sequenceselected from the group consisting of IFVINQKTG (SEQ ID NO:503),MFIINRNTG (SEQ ID NO:517) and FYLNKDTG (SEQ ID NO:531); and (b)modulates a desmoglein-mediated function.
 93. A modulating agentaccording to any one of claims 1-4, wherein the agent comprises one ormore desmocollin CAR sequences selected from the group consisting EKD,EKDT (SEQ ID NO:532), EKDTG (SEQ ID NO:533), IEKD (SEQ ID NO:534), IEKDT(SEQ ID NO:535), IEKDTG (SEQ ID NO:536), YIEKD (SEQ ID NO:537), YIEKDT(SEQ ID NO:538), YIEKDTG (SEQ ID NO:539), FYIEKD (SEQ ID NO:540),FYIEKDT (SEQ ID NO:541), FYIEKDTG (SEQ ID NO:542), LFYIEKD (SEQ IDNO:543), LFYIEKDT (SEQ ID NO:544), LFYIEKDTG (SEQ ID NO:545), ERD, ERDT(SEQ ID NO:546), ERDTG (SEQ ID NO:547), VERD (SEQ ID NO:548), VERDT (SEQID NO:549), VERDTG (SEQ ID NO:550), YVERD (SEQ ID NO:551), YVERDT (SEQID NO:552), YVERDTG (SEQ ID NO:553), FYVERD (SEQ ID NO:554), FYVERDT(SEQ ID NO:555), FYVERDTG (SEQ ID NO:556), LFYVERD (SEQ ID NO:557),LFYVERDT (SEQ ID NO:558), LFYVERDTG (SEQ ID NO:559), IERD (SEQ IDNO:560), IERDT (SEQ ID NO:561), IERDTG (SEQ ID NO:562), YIERD (SEQ IDNO:563), YIERDT (SEQ ID NO:564), YIERDTG (SEQ ID NO:565), FYIERD (SEQ IDNO:566), FYIERDT (SEQ ID NO:567), FYIERDTG (SEQ ID NO:568), LFYIERD (SEQID NO:569), LFYIERDT (SEQ ID NO:570) and LFYIERDTG (SEQ ID NO:571). 94.A modulating agent according to claim 93, wherein the agent comprises alinear peptide having the sequence N-Ac-LFYIEKDTG-NH₂ (SEQ ID NO:545),N-Ac-LFWERDTG-NH₂ (SEQ ID NO:559) or N-Ac-LFYIERDTG-NH₂ (SEQ ID NO:571).95. A modulating agent according to claim 93, wherein a desmocollin CARsequence is present within a cyclic peptide.
 96. A modulating agentaccording to claim 95, wherein the cyclic peptide comprises a sequenceselected from the group consisting of CEKDC (SEQ ID NO:3327), CEKDTC(SEQ ID NO:3328), CEKDTGC (SEQ ID NO:3329), CIEKDC (SEQ ID NO:3330),CIEKDTC (SEQ ID NO:3331), CIEKDTGC (SEQ ID NO:3332), CYIEKDC (SEQ IDNO:3333), CYIEKDTC (SEQ ID NO:3334), CYIEKDTGC (SEQ ID NO:3335),CFYIEKDC (SEQ ID NO:3336), CFYIEKDTC (SEQ ID NO:3337), CFYIEKDTGC (SEQID NO:3338), CLFYIEKDC (SEQ ID NO:3339), CLFYIEKDTC (SEQ ID NO:3340),CLFYIEKDTGC (SEQ ID NO:3341), CERDC (SEQ ID NO:3342), CERDTC (SEQ IDNO:3343), CERDTGC (SEQ ID NO:3344), CVERDC (SEQ ID NO:3345), CVERDTC(SEQ ID NO:3346), CVERDTGC (SEQ ID NO:3347), CYVERDC (SEQ ID NO:3348),CYVERDTC (SEQ ID NO:3349), CYVERDTGC (SEQ ID NO:3350), CFYVERDC (SEQ IDNO:3351), CFYVERDTC (SEQ ID NO:3352), CFYVERDTGC (SEQ ID NO:3353),CLFYVERDC (SEQ ID NO:3354), CLFYVERDTC (SEQ ID NO:3355), CLFYVERDTGC(SEQ ID NO:3356), CIERDC (SEQ ID NO:3357), CIERDTC (SEQ ID NO:3358),CIERDTGC (SEQ ID NO:3359), CYIERDC (SEQ ID NO:3360), CYIERDTC (SEQ IDNO:3361), CYIERDTGC (SEQ ID NO:3362), CFYIERDC (SEQ ID NO:3363),CFYIERDTC (SEQ ID NO:3364), CFYIERDTGC (SEQ ID NO:3365), CLFYIERDC (SEQID NO:3366), CLFYIERDTC (SEQ ID NO:3367), CLFYIERDTGC (SEQ ID NO:3368),EEKDK (SEQ ID NO:3369), EEKDTK (SEQ ID NO:3370), EEKDTGK (SEQ IDNO:3371), EIEKDK (SEQ ID NO:3372), EIEKDTK (SEQ ID NO:3373), EIEKDTGK(SEQ ID NO:3374), EYIEKDK (SEQ ID NO:3375), EYIEKDTK (SEQ ID NO:3376),EYIEKDTGK (SEQ ID NO:3377), EFYIEKDK (SEQ ID NO:3378), EFYIEKDTK (SEQ IDNO:3379), EFYIEKDTGK (SEQ ID NO:3380), ELFYIEKDK (SEQ ID NO:3381),ELFYIEKDTK (SEQ ID NO:3382), ELFYIEKDTGK (SEQ ID NO:3383), EERDK (SEQ IDNO:3384), EERDTK (SEQ ID NO:3385), EERDTGK (SEQ ID NO:3386), EVERDK (SEQID NO:3387), EVERDTK (SEQ ID NO:3388), EVERDTGK (SEQ ID NO:3389),EYVERDK (SEQ ID NO:3390), YVERDTK (SEQ ID NO:3391), EYVERDTGK (SEQ IDNO:3392), EFYVERDK (SEQ ID NO:3393), EFWERDTK (SEQ ID NO:3394),EFYVERDTGK (SEQ ID NO:3395), ELFYVERDK (SEQ ID NO:3396), ELFYVERDTK (SEQID NO:3397), ELFYVERDTGK (SEQ ID NO:3398), EIERDK (SEQ ID NO:3399),EIERDTK (SEQ ID NO:3400), EIERDTGK (SEQ ID NO:3401), EYIERDK (SEQ IDNO:3402), EYIERDTK (SEQ ID NO:3403), EYIERDTGK (SEQ ID NO:3404),EFYIERDK (SEQ ID NO:3405), EFYIERDTK (SEQ ID NO:3406), EFYIERDTGK (SEQID NO:3407), ELFYIERDK (SEQ ID NO:3408), ELFYIERDTK (SEQ ID NO:3409),ELFYIERDTGK (SEQ ID NO:3410), KEKDD (SEQ ID NO:3411), KEKDTD (SEQ IDNO:3412), KEKDTGD (SEQ ID NO:3413), KIEKDD (SEQ ID NO:3414), KIEKDTD(SEQ ID NO:3415), KIEKDTGD (SEQ ID NO:3416), KYIEKDD (SEQ ID NO:3417),KYIEKDTD (SEQ ID NO:3418), KYIEKDTGD (SEQ ID NO:3419), KFYIEKDD (SEQ IDNO:3420), KFYIEKDTD (SEQ ID NO:3421), KFYIEKDTGD (SEQ ID NO:3422),KLFYIEKDD (SEQ ID NO:3423), KLFYIEKDTD (SEQ ID NO:3424), KLFYIEKDTGD(SEQ ID NO:3425), KERDD (SEQ ID NO:3426), KERDTD (SEQ ID NO:3427),KERDTGD (SEQ ID NO:3428), KVERDD (SEQ ID NO:3429), KVERDTD (SEQ IDNO:3430), KVERDTGD (SEQ ID NO:3431), KYVERDD (SEQ ID NO:3432), KYVERDTD(SEQ ID NO:3433), KYVERDTGD (SEQ ID NO:3434), KFYVERDD (SEQ ID NO:3435),KFYVERDTD (SEQ ID NO:3436), KFYVERDTGD (SEQ ID NO:3437), KLFYVERDD (SEQID NO:3438), KLFYVERDTD (SEQ ID NO:3439), KLFYVERDTGD (SEQ ID NO:3440),KIERDD (SEQ ID NO:3441), KIERDTD (SEQ ID NO:3442), KIERDTGD (SEQ IDNO:3443), KYIERD (SEQ ID NO:3444), KYIERDTD (SEQ ID NO:3445), KYIERDTGD(SEQ ID NO:3446), KFYIERDD (SEQ ID NO:3447), KFYIERDTD (SEQ ID NO:3448),KFYIERDTGD (SEQ ID NO:3449), KLFYIERDD (SEQ ID NO:3450), KLFYIERDTD (SEQID NO:3451), KLFYIERDTGD (SEQ ID NO:3452), DEKDK (SEQ ID NO:3453),DEKDTK (SEQ ID NO:3454), DEKDTGK (SEQ ID NO:3455), DIEKDK (SEQ IDNO:3456), DIEKDTK (SEQ ID NO:3457), DIEKDTGK (SEQ ID NO:3458), DYIEKDK(SEQ ID NO:3459), DYIEKDTK (SEQ ID NO:3460), DYIEKDTGK (SEQ ID NO:3461),DFYIEKDK (SEQ ID NO:3462), DFYIEKDTK (SEQ ID NO:3463), DFYIEKDTGK (SEQID NO:3464), DLFYIEKDK (SEQ ID NO:3465), DLFYIEKDTK (SEQ ID NO:3466),DLFYIEKDTGK (SEQ ID NO:3467), DERDK (SEQ ID NO:3468), DERDTK (SEQ IDNO:3469), DERDTGK (SEQ ID NO:3470), DVERDK (SEQ ID NO:3471), DVERDTK(SEQ ID NO:3472), DVERDTGK (SEQ ID NO:3473), DYVERDK (SEQ ID NO:3474),DWERDTK (SEQ ID NO:3475), DYVERDTGK (SEQ ID NO:3476), DFYVERDK (SEQ IDNO:3477), DFYVERDTK (SEQ ID NO:3478), DFYVERDTGK (SEQ ID NO:3479),DLFYVERDK (SEQ ID NO:3480), DLFYVERDTK (SEQ ID NO:3481), DLFYVERDTGK(SEQ ID NO:3482), DIERDK (SEQ ID NO:3483), DIERDTK (SEQ ID NO:3484),DIERDTGK (SEQ ID NO:3485), DYIERDK (SEQ ID NO:3486), DYIERDTK (SEQ IDNO:3487), DYIERDTGK (SEQ ID NO:3488), DFYIERDK (SEQ ID NO:3489),DFYIERDTK (SEQ ID NO:3490), DFYIERDTGK (SEQ ID NO:3491), DLFYIERDK (SEQID NO:3492), DLFYIERDTK (SEQ ID NO:3493), DLFYIERDTGK (SEQ ID NO:3494),KEKDE (SEQ ID NO:3495), KEKDTE (SEQ ID NO:3496), KEKDTGE (SEQ IDNO:3497), KIEKDE (SEQ ID NO:3498), KIEKDTE (SEQ ID NO:3499), KIEKDTGE(SEQ ID NO:3500), KYIEKDE (SEQ ID NO:3501), KYIEKDTE (SEQ ID NO:3502),KYIEKDTGE (SEQ ID NO:3503), KFYIEKDE (SEQ ID NO:3504), KFYIEKDTE (SEQ IDNO:3505), KFYIEKDTGE (SEQ ID NO:3506), KLFYIEKDE (SEQ ID NO:3507),KLFYIEKDTE (SEQ ID NO:3508), KLFYIEKDTGE (SEQ ID NO:3509), KERDE (SEQ IDNO:3510), KERDTE (SEQ ID NO:3511), KERDTGE (SEQ ID NO:3512), KVERDE (SEQID NO:3513), KVERDTE (SEQ ID NO:3514), KVERDTGE (SEQ ID NO:3515),KYVERDE (SEQ ID NO:3516), KYVERDTE (SEQ ID NO:3517), KYVERDTGE (SEQ IDNO:3518), KFYVERDE (SEQ ID NO:3519), KFYVERDTE (SEQ ID NO:3520),KFYVERDTGE (SEQ ID NO:3521), KLFYVERDE (SEQ ID NO:3522), KLFYVERDTE (SEQID NO:3523), KLFYVERDTGE (SEQ ID NO:3524), KIERDE (SEQ ID NO:3525),KIERDTE (SEQ ID NO:3526), KIERDTGE (SEQ ID NO:3527), KYIERDE (SEQ IDNO:3528), KYIERDTE (SEQ ID NO:3529), KYIERDTGE (SEQ ID NO:3530),KFYIERDE (SEQ ID NO:3531), KFYIERDTE (SEQ ID NO:3532), KFYIERDTGE (SEQID NO:3533), KLFYIERDE (SEQ ID NO:3534), KLFYIERDTE (SEQ ID NO:3535),KLFYIERDTGE (SEQ ID NO:3536), EKDTG (SEQ ID NO:3537), IEKDT (SEQ IDNO:3538), IEKDTG (SEQ ID NO:3539), YIEKD (SEQ ID NO:3540), YIEKDT (SEQID NO:3541), YIEKDTG (SEQ ID NO:3542), FYIEKD (SEQ ID NO:3543), FYIEKDT(SEQ ID NO:3544), FYIEKDTG (SEQ ID NO:3545), LFYIEKD (SEQ ID NO:3546),LFYIEKDT (SEQ ID NO:3547), LFYIEKDTG (SEQ ID NO:3548), ERDTG (SEQ IDNO:3549), VERDT (SEQ ID NO:3550), VERDTG (SEQ ID NO:3551), YVERD (SEQ IDNO:3552), YVERDT (SEQ ID NO:3553), YVERDTG (SEQ ID NO:3554), FYVERD (SEQID NO:3555), FYVERDT (SEQ ID NO:3556), FYVERDTG (SEQ ID NO:3557),LFYVERD (SEQ ID NO:3558), LFYVERDT (SEQ ID NO:3559), LFYVERDTG (SEQ IDNO:3560), IERDT (SEQ ID NO:3561), IERDTG (SEQ ID NO:3562), YIERD (SEQ IDNO:3563), YIERDT (SEQ ID NO:3564), YIERDTG (SEQ ID NO:3565), FYIERD (SEQID NO:3566), FYIERDT (SEQ ID NO:3567), FYIERDTG (SEQ ID NO:3568),LFYIERD (SEQ ID NO:3569), LFYIERDT (SEQ ID NO:3570) and LFYIERDTG (SEQID NO:3571).
 97. A polynucleotide encoding a modulating agent accordingto claim
 93. 98. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to adesmocollin CAR sequence selected from the group consisting of LFYIEKDTG(SEQ ID NO:545), LFYVERDTG (SEQ ID NO:559) and LFYIERDTG (SEQ IDNO:571); and (b) modulates a desmocollin-mediated function.
 99. Amodulating agent according to any one of claims 1-4, wherein the agentcomprises one or more cadherin-related neuronal receptor CAR sequencesselected from the group consisting of DPV, DPVS (SEQ ID NO:572), DPVSG(SEQ ID NO:573), IDPV (SEQ ID NO:574), IDPVS (SEQ ID NO:575), IDPVSG(SEQ ID NO:576), HIDPV (SEQ ID NO:577), HIDPVS (SEQ ID NO:578), HIDPVSG(SEQ ID NO:579), FHIDPV (SEQ ID NO:580), FHIDPVS (SEQ ID NO:581),FHIDPVSG (SEQ ID NO:582), KFHIDPV (SEQ ID NO:583), KFHIDPVS (SEQ IDNO:584), KFHIDPVSG (SEQ ID NO:585), DAD, DADT (SEQ ID NO:586), DADTG(SEQ ID NO:587), IDAD (SEQ ID NO:588), IDADT (SEQ ID NO:589), IDADTG(SEQ ID NO:590), SIDAD (SEQ ID NO:591), SIDADT (SEQ ID NO:592), SIDADTG(SEQ ID NO:593), FSIDAD (SEQ ID NO:594), FSIDADT (SEQ ID NO:595),FSIDADTG (SEQ ID NO:596), QFSIDAD (SEQ ID NO:597), QFSIDADT (SEQ IDNO:598), QFSIDADTG (SEQ ID NO:599), DSV, DSVS (SEQ ID NO:600), DSVSG(SEQ ID NO:601), IDSV (SEQ ID NO:602), IDSVS (SEQ ID NO:603), IDSVSG(SEQ ID NO:604), HIDSV (SEQ ID NO:605), HIDSVS (SEQ ID NO:606), HIDSVSG(SEQ ID NO:607), FHIDSV (SEQ ID NO:608), FHIDSVS (SEQ ID NO:609),FHIDSVSG (SEQ ID NO:610), TFHIDSV (SEQ ID NO:611), TFHIDSVS (SEQ IDNO:612), TFHIDSVSG (SEQ ID NO:613), DSN, DSNS (SEQ ID NO:614), DSNSG(SEQ ID NO:615), IDSN (SEQ ID NO:616), IDSNS (SEQ ID NO:617), IDSNSG(SEQ ID NO:618), NIDSN (SEQ ID NO:619), NIDSNS (SEQ ID NO:620), NIDSNSG(SEQ ID NO:621), FNIDSN (SEQ ID NO:622), FNIDSNS (SEQ ID NO:623),FNIDSNSG (SEQ ID NO:624), AFNIDSN (SEQ ID NO:625), AFNIDSNS (SEQ IDNO:626), AFNIDSNSG (SEQ ID NO:627), DSS, DSSS (SEQ ID NO:628), DSSSG(SEQ ID NO:629), IDSS (SEQ ID NO:630), IDSSS (SEQ ID NO:631), IDSSSG(SEQ ID NO:632), TIDSS (SEQ ID NO:633), TIDSSS (SEQ ID NO:634), TIDSSSG(SEQ ID NO:635), FTIDSS (SEQ ID NO:636), FTIDSSS (SEQ ID NO:637),FTIDSSSG (SEQ ID NO:638), KFTIDSS (SEQ ID NO:639), KFTIDSSS (SEQ IDNO:640), KFTIDSSSG (SEQ ID NO:641), DEK, DEKN (SEQ ID NO:642), DEKNG(SEQ ID NO:643), LDEK (SEQ ID NO:644), LDEKN (SEQ ID NO:645), LDEKNG(SEQ ID NO:646), TLDEK (SEQ ID NO:647), TLDEKN (SEQ ID NO:648), TLDEKNG(SEQ ID NO:649), FTLDEK (SEQ ID NO:650), FTLDEKN (SEQ ID NO:651),FTLDEKNG (SEQ ID NO:652), LFTLDEK (SEQ ID NO:653), LFTLDEKN (SEQ IDNO:654), LFTLDEKNG (SEQ ID NO:655), NEK, NEKT (SEQ ID NO:656), NEKTG(SEQ ID NO:657), INEK (SEQ ID NO:658), INEKT (SEQ ID NO:659), INEKTG(SEQ ID NO:660), LINEK (SEQ ID NO:661), LINEKT (SEQ ID NO:662), LINEKTG(SEQ ID NO:663), FLINEK (SEQ ID NO:664), FLINEKT (SEQ ID NO:665),FLINEKTG (SEQ ID NO:666), KFLINEK (SEQ ID NO:667), KFLINEKT (SEQ IDNO:668) and KFLINEKTG (SEQ ID NO:4052).
 100. A modulating agentaccording to claim 99, wherein the agent comprises a linear peptidehaving the sequence N-Ac-KFHIDPVSG-NH₂ (SEQ ID NO:585),N-Ac-QFSIDADTG-NH₂ (SEQ ID NO:599), N-Ac-TFHIDSVSG-NH₂ (SEQ ID NO:613),N-Ac-AFNIDSNSG-NH₂ (SEQ ID NO:627), N-Ac-KFTIDSSSG-NH₂ (SEQ ID NO:641),N-Ac-LFTLDEKNG-NH₂ (SEQ ID NO:655) or N-Ac-KFLINEKTG-NH₂ (SEQ IDNO:4052).
 101. A modulating agent according to claim 99, wherein acadherin-related neuronal receptor CAR sequence is present within acyclic peptide.
 102. A modulating agent according to claim 101, whereinthe cyclic peptide comprises a sequence selected from the groupconsisting of CDPVC (SEQ ID NO:3572), CDPVSC (SEQ ID NO:3573), CDPVSGC(SEQ ID NO:3574), CIDPVC (SEQ ID NO:3575), CIDPVSC (SEQ ID NO:3576),CIDPVSGC (SEQ ID NO:3577), CHIDPVC (SEQ ID NO:3578), CHIDPVSC (SEQ IDNO:3579), CHIDPVSGC (SEQ ID NO:3580), CFHIDPVC (SEQ ID NO:3581),CFHIDPVSC (SEQ ID NO:3582), CFHIDPVSGC (SEQ ID NO:3583), CKFHIDPVC (SEQID NO:3584), CKFHIDPVSC (SEQ ID NO:3585), CKFHIDPVSGC (SEQ ID NO:3586),CDADC (SEQ ID NO:3587), CDADTC (SEQ ID NO:3588), CDADTGC (SEQ IDNO:3589), CIDADTC (SEQ ID NO:3590), CIDADC (SEQ ID NO:3591), CIDADTGC(SEQ ID NO:3592), CSIDADC (SEQ ID NO:3593), CSIDADTC (SEQ ID NO:3594),CSIDADTGC (SEQ ID NO:3595), CFSIDADC (SEQ ID NO:3596), CFSIDADTC (SEQ IDNO:3597), CFSIDADTGC (SEQ ID NO:3598), CQFSIDADC (SEQ ID NO:3599),CQFSIDADTC (SEQ ID NO:3600), CQFSIDADTGC (SEQ ID NO:3601), CDSVC (SEQ IDNO:3602), CDSVSC (SEQ ID NO:3603), CDSVSGC (SEQ ID NO:3604), CIDSVC (SEQID NO:3605), CIDSVSC (SEQ ID NO:3606), CIDSVSGC (SEQ ID NO:3607),CHIDSVC (SEQ ID NO:3608), CHIDSVSC (SEQ ID NO:3609), CHIDSVSGC (SEQ IDNO:3610), CFHIDSVC (SEQ ID NO:3611), CFHIDSVSC (SEQ ID NO:3612),CFHIDSVSGC (SEQ ID NO:3613), CTFHIDSVC (SEQ ID NO:3614), CTFHIDSVSC (SEQID NO:3615), CTFHIDSVSGC (SEQ ID NO:3616), CDSNC (SEQ ID NO:3617),CDSNSC (SEQ ID NO:3618), CDSNSGC (SEQ ID NO:3619), CIDSNC (SEQ IDNO:3620), CIDSNSC (SEQ ID NO:3621), CIDSNSGC (SEQ ID NO:3622), CNIDSNC(SEQ ID NO:3623), CNIDSNSC (SEQ ID NO:3624), CNIDSNSGC (SEQ ID NO:3625),CFNIDSNC (SEQ ID NO:3626), CFNIDSNSC (SEQ ID NO:3627), CFNIDSNSGC (SEQID NO:3628), CAFNIDSNC (SEQ ID NO:3629), CAFNIDSNSC (SEQ ID NO:3631),CAFNIDSNSGC (SEQ ID NO:3632), CDSSC (SEQ ID NO:3633), CDSSSC (SEQ IDNO:3634), CDSSSGC (SEQ ID NO:3635), CIDSSC (SEQ ID NO:3636), CIDSSSC(SEQ ID NO:3637), CIDSSSGC (SEQ ID NO:3638), CTIDSSC (SEQ ID NO:3639),CTIDSSSC (SEQ ID NO:3640), CTIDSSSGC (SEQ ID NO:3641), CFTIDSSC (SEQ IDNO:3642), CFTIDSSSC (SEQ ID NO:3643), CFTIDSSSGC (SEQ ID NO:3644),CKFTIDSSC (SEQ ID NO:3645), CKFTIDSSSC (SEQ ID NO:3646), CKFTIDSSSGC(SEQ ID NO:3647), CDEKC (SEQ ID NO:3648), CDEKNC (SEQ ID NO:3649),CDEKNGC (SEQ ID NO:3650), CLDEKC (SEQ ID NO:3651), CLDEKNC (SEQ IDNO:3652), CLDEKNGC (SEQ ID NO:3653), CTLDEKC (SEQ ID NO:3654), CTLDEKNC(SEQ ID NO:3655), CTLDEKNGC (SEQ ID NO:3656), CFTLDEKC (SEQ ID NO:3657),CFTLDEKNC (SEQ ID NO:3658), CFTLDEKNGC (SEQ ID NO:3659), CLFTLDEKC (SEQID NO:3660), CLFTLDEKNC (SEQ ID NO:3661), CLFTLDEKNGC (SEQ ID NO:3662),CNEKC (SEQ ID NO:3663), CNEKTC (SEQ ID NO:3664), CNEKTGC (SEQ IDNO:3665), CINEKC (SEQ ID NO:3666), CINEKTC (SEQ ID NO:3667), CINEKTGC(SEQ ID NO:3668), CLINEKC (SEQ ID NO:3669), CLINEKTC (SEQ ID NO:3670),CLINEKTGC (SEQ ID NO:3671), CFLINEKC (SEQ ID NO:3672), CFLINEKTC (SEQ IDNO:3673), CFLINEKTGC (SEQ ID NO:3674), CKFLINEKC (SEQ ID NO:3675),CKFLINEKTC (SEQ ID NO:3676), CKFLINEKTGC (SEQ ID NO:3677), EDPVK (SEQ IDNO:3678), EDPVSK (SEQ ID NO:3679), EDPVSGK (SEQ ID NO:3680), EIDPVK (SEQID NO:3681), EIDPVSK (SEQ ID NO:3682), EIDPVSGK (SEQ ID NO:3683),EHIDPVK (SEQ ID NO:3684), EHIDPVSK (SEQ ID NO:3685), EHIDPVSGK (SEQ IDNO:3686), EFHIDPVK (SEQ ID NO:3687), EFHIDPVSK (SEQ ID NO:3688),EFHIDPVSGK (SEQ ID NO:3689), EKFHIDPVK (SEQ ID NO:3690), EKFHIDPVSK (SEQID NO:3691), EKFHIDPVSGK (SEQ ID NO:3692), EDADK (SEQ ID NO:3693),EDADTK (SEQ ID NO:3694), EDADTGK (SEQ ID NO:3695), EIDADK (SEQ IDNO:3696), EIDADTK (SEQ ID NO:3697), EIDADTGK (SEQ ID NO:3698), ESIDADK(SEQ ID NO:3699), ESIDADTK (SEQ ID NO:3700), ESIDADTGK (SEQ ID NO:3701),EFSIDADK (SEQ ID NO:3702), EFSIDADTK (SEQ ID NO:3703), EFSIDADTGK (SEQID NO:3704), EQFSIDADK (SEQ ID NO:3705), EQFSIDADTK (SEQ ID NO:3706),EQFSIDADTGK (SEQ ID NO:3707), EDSVK (SEQ ID NO:3708), EDSVSK (SEQ IDNO:3709), EDSVSGK (SEQ ID NO:3710), EIDSVK (SEQ ID NO:3711), EIDSVSK(SEQ ID NO:3712), EIDSVSGK (SEQ ID NO:3713), EHIDSVK (SEQ ID NO:3714),EHIDSVSK (SEQ ID NO:3715), EHIDSVSGK (SEQ ID NO:3716), EFHIDSVK (SEQ IDNO:3717), EFHIDSVSK (SEQ ID NO:3718), EFHIDSVSGK (SEQ ID NO:3719),ETFHIDSVK (SEQ ID NO:3720), ETFHIDSVSK (SEQ ID NO:3721), ETFHIDSVSGK(SEQ ID NO:3722), EDSNK (SEQ ID NO:3723), EDSNSK (SEQ ID NO:3724),EDSNSGK (SEQ ID NO:3725), EIDSNK (SEQ ID NO:3726), EIDSNSK (SEQ IDNO:3727), EIDSNSGK (SEQ ID NO:3728), ENIDSNK (SEQ ID NO:3729), ENIDSNSK(SEQ ID NO:3730), ENIDSNSGK (SEQ ID NO:3731), EFNIDSNK (SEQ ID NO:3732),EFNIDSNSK (SEQ ID NO:3733), EFNIDSNSGK (SEQ ID NO:3734), EAFNIDSNK (SEQID NO:3735), EAFNIDSNSK (SEQ ID NO:3737), EAFNIDSNSGK (SEQ ID NO:3738),EDSSK (SEQ ID NO:3739), EDSSSK (SEQ ID NO:3740), EDSSSGK (SEQ IDNO:3741), EIDSSK (SEQ ID NO:3742), EIDSSSK (SEQ ID NO:3743), EIDSSSGK(SEQ ID NO:3744), ETIDSSK (SEQ ID NO:3745), ETIDSSSK (SEQ ID NO:3746),ETIDSSSGK (SEQ ID NO:3747), EFTIDSSK (SEQ ID NO:3748), EFTIDSSSK (SEQ IDNO:3749), EFTIDSSSGK (SEQ ID NO:3750), EKFTIDSSK (SEQ ID NO:3751),EKFTIDSSSK (SEQ ID NO:3752), EKFTIDSSSGK (SEQ ID NO:3753), EDEKK (SEQ IDNO:3754), EDEKNK (SEQ ID NO:3755), EDEKNGK (SEQ ID NO:3756), ELDEKK (SEQID NO:3757), ELDEKNK (SEQ ID NO:3758), ELDEKNGK (SEQ ID NO:3759),ETLDEKK (SEQ ID NO:3760), ETLDEKNK (SEQ ID NO:3761), ETLDEKNGK (SEQ IDNO:3762), EFTLDEKK (SEQ ID NO:3763), EFTLDEKNK (SEQ ID NO:3764),EFTLDEKNGK (SEQ ID NO:3765), ELFTLDEKK (SEQ ID NO:3766), ELFTLDEKNK (SEQID NO:3767), ELFTLDEKNGK (SEQ ID NO:3768), ENEKK (SEQ ID NO:3769),ENEKTK (SEQ ID NO:3770), ENEKTGK (SEQ ID NO:3771), EINEKK (SEQ IDNO:3772), EINEKTK (SEQ ID NO:3773), EINEKTGK (SEQ ID NO:3774), ELINEKK(SEQ ID NO:3775), ELINEKTK (SEQ ID NO:3776), ELINEKTGK (SEQ ID NO:3777),EFLINEKK (SEQ ID NO:3778), EFLINEKTK (SEQ ID NO:3779), EFLINEKTGK (SEQID NO:3780), EKFLINEKK (SEQ ID NO:3781), EKFLINEKTK (SEQ ID NO:3782),EKFLINEKTGK (SEQ ID NO:3783), KDPVD (SEQ ID NO:3784), KDPVSD (SEQ IDNO:3785), KDPVSGD (SEQ ID NO:3786), KIDPVD (SEQ ID NO:3787), KIDPVSD(SEQ ID NO:3788), KIDPVSGD (SEQ ID NO:3789), KHIDPVD (SEQ ID NO:3790),KHIDPVSD (SEQ ID NO:3791), KHIDPVSGD (SEQ ID NO:3792), KFHIDPVD (SEQ IDNO:3793), KFHIDPVSD (SEQ ID NO:3794), KFHIDPVSGD (SEQ ID NO:3795),KKFHIDPVD (SEQ ID NO:3796), KKFHIDPVSD (SEQ ID NO:3797), KKFHIDPVSGD(SEQ ID NO:3798), KDADD (SEQ ID NO:3799), KDADTD (SEQ ID NO:3800),KDADTGD (SEQ ID NO:3801), KIDADD (SEQ ID NO:3802), KIDADTD (SEQ IDNO:3803), KIDADTGD (SEQ ID NO:3804), KSIDADD (SEQ ID NO:3805), KSIDADTD(SEQ ID NO:3806), KSIDADTGD (SEQ ID NO:3807), KFSIDADD (SEQ ID NO:3808),KFSIDADTD (SEQ ID NO:3809), KFSIDADTGD (SEQ ID NO:3810), KQFSIDADD (SEQID NO:3811), KQFSIDADTD (SEQ ID NO:3812), KQFSIDADTGD (SEQ ID NO:3813),KDSVD (SEQ ID NO:3814), KDSVSD (SEQ ID NO:3815), KDSVSGD (SEQ IDNO:3816), KIDSVD (SEQ ID NO:3817), KIDSVSD (SEQ ID NO:3818), KIDSVSGD(SEQ ID NO:3819), KHIDSVD (SEQ ID NO:3820), KHIDSVSD (SEQ ID NO:3821),KHIDSVSGD (SEQ ID NO:3822), KFHIDSVD (SEQ ID NO:3823), KFHIDSVSD (SEQ IDNO:3824), KFHIDSVSGD (SEQ ID NO:3825), KTFHIDSVD (SEQ ID NO:3826),KTFHIDSVSD (SEQ ID NO:3827), KTFHIDSVSGD (SEQ ID NO:3828), KDSND (SEQ IDNO:3829), KDSNSD (SEQ ID NO:3830), KDSNSGD (SEQ ID NO:3831), KIDSND (SEQID NO:3832), KIDSNSD (SEQ ID NO:3833), KIDSNSGD (SEQ ID NO:3834),KNIDSND (SEQ ID NO:3835), KNIDSNSD (SEQ ID NO:3836), KNIDSNSGD (SEQ IDNO:3837), KFNIDSND (SEQ ID NO:3838), KFNIDSNSD (SEQ ID NO:3839),KFNIDSNSGD (SEQ ID NO:3840), KAFNIDSND (SEQ ID NO:3841), KAFNIDSNSD (SEQID NO:3843), KAFNIDSNSGD (SEQ ID NO:3844), KDSSD (SEQ ID NO:3845),KDSSSD (SEQ ID NO:3846), KDSSSGD (SEQ ID NO:3847), KIDSSD (SEQ IDNO:3848), KIDSSSD (SEQ ID NO:3849), KIDSSSGD (SEQ ID NO:3850), KTIDSSD(SEQ ID NO:3851), KTIDSSSD (SEQ ID NO:3852), KTIDSSSGD (SEQ ID NO:3853),KFTIDSSD (SEQ ID NO:3854), KFTIDSSSD (SEQ ID NO:3855), KFTIDSSSGD (SEQID NO:3856), KKFTIDSSD (SEQ ID NO:3857), KKFTIDSSSD (SEQ ID NO:3858),KKFTIDSSSGD (SEQ ID NO:3859), KDEKD (SEQ ID NO:3860), KDEKND (SEQ IDNO:3861), KDEKNGD (SEQ ID NO:3862), KLDEKD (SEQ ID NO:3863), KLDEKND(SEQ ID NO:3864), KLDEKNGD (SEQ ID NO:3865), KTLDEKD (SEQ ID NO:3866),KTLDEKND (SEQ ID NO:3867), KTLDEKNGD (SEQ ID NO:3868), KFTLDEKD (SEQ IDNO:3869), KFTLDEKND (SEQ ID NO:3870), KFTLDEKNGD (SEQ ID NO:3871),KLFTLDEKD (SEQ ID NO:3872), KLFTLDEKND (SEQ ID NO:3873), KLFTLDEKNGD(SEQ ID NO:3874), KNEKD (SEQ ID NO:3875), KNEKTD (SEQ ID NO:3876),KNEKTGD (SEQ ID NO:3877), KINEKD (SEQ ID NO:3878), KINEKTD (SEQ IDNO:3879), KINEKTGD (SEQ ID NO:3880), KLINEKD (SEQ ID NO:3881), KLINEKTD(SEQ ID NO:3882), KLINEKTGD (SEQ ID NO:3883), KFLINEKD (SEQ ID NO:3884),KFLINEKTD (SEQ ID NO:3885), KFLINEKTGD (SEQ ID NO:3886), KKFLINEKD (SEQID NO:3887), KKFLINEKTD (SEQ ID NO:3888) and KKFLINEKTGD (SEQ IDNO:3889).
 103. A polynucleotide encoding a modulating agent according toclaim
 99. 104. A modulating agent comprising an antibody orantigen-binding fragment thereof that: (a) specifically binds to acadherin-related neuronal receptor CAR sequence selected from the groupconsisting of KFHIDPVSG (SEQ ID NO:585), QFSIDADTG (SEQ ID NO:599),TFHIDSVSG (SEQ ID NO:613), AFNIDSNSG (SEQ ID NO:627), KFTIDSSSG (SEQ IDNO:641), LFTLDEKNG (SEQ ID NO:655) and KFLINEKTG (SEQ ID NO:4052); and(b) modulates a cadherin-related neuronal receptor-mediated function.105. A modulating agent according to any one of claims 1-4 or 12-14linked to a drug.
 106. A modulating agent according to any one of claims1-4 or 12-14 linked to a detectable marker.
 107. A modulating agentaccording to any one of claims 1-4 or 12-14 linked to a targeting agent.108. A modulating agent according to any one of claims 1-4 or 12-14linked to a support material.
 109. A modulating agent according to claim108, wherein the support material is a polymeric matrix.
 110. Amodulating agent according to claim 108, wherein the support material isselected from the group consisting of plastic dishes, plastic tubes,sutures, membranes, ultra thin films, bioreactors and microparticles.111. A modulating agent according to any one of claims 1-4 or 12-14,further comprising one or more of: (a) a CAR sequence that isspecifically recognized by an adhesion molecule other than thenonclassical cadherin; and/or (b) an antibody or antigen-bindingfragment thereof that specifically binds to a CAR sequence that isspecifically recognized by an adhesion molecule other than thenonclassical cadherin.
 112. A modulating agent according to claim 111,wherein the adhesion molecule is selected from the group consisting ofcadherins, integrins, occludin, claudins, desmogleins, desmocollins,protocadherins, cadherin-related neuronal receptors, fibronectin,laminin, claudins and other extracellular matrix proteins.
 113. Apharmaceutical composition comprising a modulating agent according toany one of claims 1-4 or 12-14 in combination with a pharmaceuticallyacceptable carrier.
 114. A composition according to claim 113, furthercomprising a drug.
 115. A composition according to claim 113, whereinthe modulating agent is present within a sustained-release formulation.116. A pharmaceutical composition according to claim 115, furthercomprising a modulator of cell adhesion that comprises one or more of:(a) a CAR sequence that is specifically recognized by an adhesionmolecule other than the nonclassical cadherin; and/or (b) an antibody orantigen-binding fragment thereof that specifically binds to a CARsequence that is specifically recognized by an adhesion molecule otherthan the nonclassical cadherin.
 117. A pharmaceutical compositionaccording to claim 116, wherein the adhesion molecule is selected fromthe group consisting of cadherins, integrins, occludin, claudins,desmogleins, desmocollins, protocadherins, cadherin-related neuronalreceptors, fibronectin, laminin and other extracellular matrix proteins.